Dairylalkanoids having activity as lipoxygenase inhibitors

ABSTRACT

The present invention is novel diarylalkanoids having activity as lipoxygenase inhibitors, novel pharmaceutical compositions therefor, and novel methods of use in treating asthma, allergies, cardiovascular diseases, migrains, psoriasis and immunoinflammatory diseases for diarylalkanoids. The compounds of this invention are also useful as cytoprotective agents.

This is a divisional of U.S. application Ser. No. 07/266,035 filed Nov.2, 1988, now U.S. Pat. No. 4,959,503, which is a continuation-in-part ofU.S. application Ser. No. 16,897, filed Mar. 3, 1987, now U.S. Pat. No.4,810,716 which is a continuation-in-part of U.S. Pat. application Ser.No. 851,003 filed Apr. 11, 1986, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to novel compounds, pharmaceuticalcompositions and methods of use for the treatment of diseases in which5-lipoxygenase enzyme activity contributes to the pathologicalcondition. Thus, the novel compounds of the present invention haveactivity useful for treating asthma, allergies, cardiovascular diseases,migraines, psoriasis, immunoinflammatory conditions, and ascytoprotective agents.

More particularly the novel compounds having the formula I as definedbelow inhibit 5-lipoxygenase enzymes. Lipoxygenase pathway products suchas the leukotrienes B4, C4, D4, and E4, 5-hydroxyeicosatetraenoic acid,5-hydroperoxyeicosatetraenoic acid, and 12-hydroxyeicosatraenoic acidare related to the above described conditions. Specific conditions foruse of the present novel lipoxygenase-inhibiting compounds,pharmaceutical compositions thereof and the novel method of use inaccordance with the present invention include allergy; asthma;arthritis; skin disorders including psoriasis and acne;inflammation--including inflammatory bowel diseases or pain; andcardiovascular disorders including myocardial ischemia and infarction,angina, arrhythmias, stroke, migraine and atherosclerosis.

Itokawa, H. et al, "Synthesis of Diarylheptanoids and Assessment ofTheir Pungency," Chem. Pharm. Bull., 31, 2491 (1983) and "A PungentPrinciple from Alpina Oxyphylla," Phytochemistry, 21, 241 (1982)disclose compounds: ##STR1## wherein Q₁ and Q₂ are independentlyhydrogen, hydroxy or methoxy, correlating structure and pungency withpreviously published pain-producing experiments on capsaicin congeners.

European Patent Application 163270A also discloses analogs of compoundA.

Itokawa, H. et al, "Two New Diarylheptanoids from Alpinia OffcinarumHance," Chem. Pharm. Bull., 29(8) 2383-5 (1981) disclose a compound fromthose of formula B above as a fraction of an extract which extract wasused in Chinese medicine to relieve gastrointestinal disorders as wellas fractions of which were known to contract the ileum of guinea pigs.Further, prostaglandin-biosynthesis inhibition having use as anantiinflammatory, antipyretic, analgesic or antiarteriosclerotic isdisclosed in J5 9098-026-A (Derivent Abstract No. 84-178335/29) for thecompound C as follows: ##STR2## wherein Q₁ and Q₂ are within the groupsdefined above therefor and Q₂ is hydrogen or together with

Q₄ is ##STR3## Q₅ and Q₆ are hydrogen, optionally form a double bondbetween the 5- and 4-position carbon or together are ##STR4##

Finally, European Patent Application 149,242 discloses a compound offormula D: ##STR5## in which Q₇ is hydrogen, alkyl, COQ₉ or CONHQ₉wherein Q₉ is an aliphatic or an aromatic group, R is alkyl or aralkyl,and the phenyl to which ##STR6## attaches may be substituted at the 2-,and/or 4-position by alkyl or chlorine and at the 3-position by alkyl orOQ' wherein Q' is alkyl, cycloalkyl or aralkyl. The compounds of formulaD are said to be useful as lipoxygenase inhibitors.

However, the present novel compounds, pharmaceutical compositions andnovel methods of using compounds as defined in the present invention arecombinations of substituents on various moieties that are not taught orare unobvious from the very limited disclosures of the above references.The compounds of the limited disclosures are excluded herein.

Of lesser interest are diaryl containing compounds linked by carbonshaving 2 alternating oxygen containing carbons. These compounds arerelated to curcumin and are disclosed in the European Patent Application149,242 noted above; by Rao, et al in "Antiinflammatory Activity ofCurcumin Analogues," Indian J. Med. Res., 75 574-8 (April 1982), and byPabon, "A Synthesis of Curcumin and Related Compounds," Recueil, 83379-386 (1964).

SUMMARY OF THE INVENTION

The present invention is a novel compound of the formula: ##STR7## orpharmaceutically acceptable base or acid addition salts thereof, wherein

(a) R₁ is (i) hydroxy, (ii) lower alkoxy, (iii) COOR₃ wherein R₃ ishydrogen or lower alkyl, (iv) lower alkanoyl, (v) NR.sub. R₄ wherein R₃and R₄ are independently hydrogen or lower alkyl, ##STR8## wherein R₃ isindependently as defined above, ##STR9## wherein R₃ is independently asdefined above, ##STR10## wherein R₃ is independently as defined above,or ##STR11## wherein R₃ is independently as defined above; (b) R₂ is (i)hydroxy, (ii) lower alkoxy, (iii) lower thioalkoxy, (iv) lower alkanoyl,(v) halogen, (vi) trifluoromethyl, (vii) hydroxymethyl, (viii) loweralkyl, (ix) NR₃ R₄ wherein R₃ and R₄ are independently hydrogen or loweralkyl, (x) nitro, ##STR12## wherein R₃ is independently as defined above##STR13## wherein R₃ is independently as defined above, ##STR14##wherein R₃ is independently as defined above, ##STR15## wherein R₃ isindependently as defined above, or ##STR16## wherein R₃ is independentlyas defined above; (c) T is (i) hydrogen, (ii) lower alkyl, (iii)hydroxy, (iv) lower alkanoyl, (v) NR₃ R₄ wherein R₃ and R₄ areindependently as defined above, (vi) nitro, (vii) halogen, (viii)trifluoromethyl, (ix) lower alkoxy, (x) lower thioalkoxy, ##STR17##wherein R₃ is independently as defined above, ##STR18## wherein R₃ isindependently as defined above, or ##STR19## wherein R₃ is independentlyas defined above, ##STR20## wherein R₃ is as defined above; (d) Z is (i)oxygen, (ii) sulfur, (iii) NOR₃ wherein R₃ is independently as definedabove, or (iv) NH;

(e) X and Y are independently (i) (CH₂)_(n), (ii) CH=CH, (iii) (CH₂)_(n)M, wherein n is an integer of one to four and M is oxygen, NR₃ whereinR₃ is independently as defined above, or S(O)q wherein q is zero, one ortwo, or (iv) CH=CH(CO₂ R₃) wherein R₃ is independently as defined above;

(f) Ar is (i) phenyl or naphthyl each of which is unsubstituted orsubstituted by one, two or three substituents comprising one or more ofeach of lower alkyl, hydroxy, lower alkoxy, lower thioalkoxy, loweralkanoyl, halogen, trifluoromethyl, lower carboalkoxy, hydroxymethyl,NR₃ R₄ wherein R₃ and R₄ are independently as defined above, nitro, COR₃wherein R₃ is independently as defined above, or ##STR21## wherein R₃and R₄ are independently as defined above, or (ii) a heteroarylunsubstituted or substituted on one or two carbons by one or more ofeach of lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, lowercarboalkoxy, halogen, trifluoromethyl, hydroxymethyl, NR₃ R₄ wherein R₃and R₄ are independently as defined above, ##STR22## wherein R₃ isindependently as defined above or CHCOR₄

wherein R₃ and R₄ are independently as defined above; in which theheteroaryl comprises pyrrolyl, furanyl, thiophenyl, oxazolyl, thiazolyl,imidazolyl, isothiazolyl, isoxazolyl, or pyrazolyl; and with the overallproviso that when T is hydrogen, R₁ is hydroxy or methoxy, R₂ ishydroxy, lower alkyl, or lower alkoxy, X is (CH₂)_(n) or CH=CH, Y is(CH₂)_(n), and Ar is phenyl or phenyl substituted by lower alkyl then Zcannot be oxygen.

The present invention also relates to a pharmaceutical composition fortreating a disease such as allergy, asthma, arthritis, psoriasis, acne,inflammation, pain, ulcerogenic, or cardiovascular disorders comprisingan antiallergy, antiasthma, antiarthritis, antipsoriatic, antiacne,antiinflammatory, analgesic, cytoprotective or cardiovascularbeneficially effective amount of the compound I as defined above with apharmaceutically acceptable carrier, and to a method of treating amammal having one of the diseases noted above by administering to suchmammals a dosage form of a compound of the formula I wherein R₁, R₂, T,Z, X, Y and Ar are as defined above but with the proviso limited only toexclude compounds where R₁ is hydroxy or lower alkoxy, R₂ is hydroxy,lower alkyl, or lower alkoxy, or X is (CH₂)_(n) and T is hydrogen, Y is(C₂)_(n), and Ar is phenyl or phenyl substituted by lower alkyl whenoverall Z is oxygen.

Finally, the present invention is a process for preparing compounds offormula I as defined above.

DETAILED DESCRIPTION OF THE EMBODIMENTS

In the compounds of formula I the term "lower alkyl" is meant to includea straight or branched alkyl group having one to four carbon atoms, suchas, for example, methyl, ethyl, propyl, or butyl and isomers thereof.

Halogen includes particularly fluorine, chlorine or bromine.

Lower alkoxy and thioalkoxy are O-alkyl or S-alkyl, respectively, offrom one to four carbon atoms as defined above for "lower alkyl".

Lower alkanoyl is a ##STR23## lower alkyl group having lower alkyl asdefined above.

Appropriate compounds of formula I are useful in the free base form, inthe form of base salts where possible, and in the form of acid additionsalts. The three forms are within the scope of the invention. Inpractice, use of salt form amounts to use of the base form.Pharmaceutically acceptable salts within the scope of the invention arethose derived from mineral acids such as hydrochloric acid and sulfuricacid; and organic acids such as ethanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, and the like, giving the hydrochloride,sulfamate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, andthe like, respectively or those derived from bases such as suitableorganic and inorganic bases. Examples of suitable inorganic bases forthe formation of salts of compounds of this invention include thehydroxides, carbonates, and bicarbonates of ammonia, sodium, lithium,potassium, calcium, magnesium, aluminum, zinc, and the like.

Salts may also be formed with suitable organic bases. Bases suitable forthe formation of pharmaceutically acceptable base addition salts withcompounds of the present invention include organic bases which arenontoxic and strong enough to form such salts. These organic bases forma class whose limits are readily understood by those skilled in the art.Merely for purposes of illustration, the class may be said to includemono-, di-, and trialkylamines, such as methylamine, dimethylamine, andtriethylamine; mono-, di- or trihydroxyalkylamines such as mono-, di-andtriethanolamine; amino acids such as arginine, and lysine; guanidine;N-methylglucosamine; N-methylglucamine; L-glutamine; N-methylpiperazine;morpholine; ethylenediamine; N-benzylphenethylamine;tris(hydroxymethyl)aminomethane; and the like. (See for example,"Pharmaceutical Salts," J. Pharm. Sci. 66(1):1-19 (1977).)

The acid addition salts of said basic compounds are prepared either bydissolving the free base of compound I in aqueous or aqueous alcoholsolution or other suitable solvents containing the appropriate acid orbase and isolating the salt by evaporating the solution, or by reactingthe free base of compound I with an acid as well as reacting compound Ihaving an acid group thereon with a base such that the reactions are inan organic solvent, in which case the salt separates directly or can beobtained by concentration of the solution.

The compounds of the invention may contain an asymmetric carbon atom.Thus, the invention includes the individual stereoisomers, and mixturesthereof. The individual isomers may be prepared or isolated by methodsknown in the art.

Compounds of the present invention that are preferred are of formula Iwherein Z is oxygen or NOR₃ wherein R₃ is hydrogen and Y is (CH₂)₂.

More preferred compounds of the present invention are the preferredcompounds of formula I wherein Z is oxygen, R₁ is hydroxy and R₂ ishalogen or trifluoromethyl.

Most preferred compounds of the present invention are as follows:

1-Pentene-3-one, 1-(3-amino-4-hydroxyphenyl)-5-phenyl;

1-Hepten-3-one, 1-(4-hydroxy-3-methoxyphenyl)-7-phenyl, oxime;

1-Hepten-3-one, 1-(3,4-dihydroxyphenyl)-7-phenyl, oxime;

1-Penten-3-one, 1-(4-hydroxy-3-methoxyphenyl)-5-phenyl, oxime;

1-Penten-3-one, 1-(3-amino-4-hydroxyphenyl)-5-phenyl, oxime, (bothisomer A and isomer B);

1-(4-Hydroxy-3-methoxyphenyl)-4-phenoxy-1-buten-3-one oxime;

1-(4-Hydroxy-3-methoxyphenyl)-6-phenoxy-1-hexen-3-one oxime; and

1-(4-Hydroxy-3-methoxyphenyl)-7-phenyl-1-hepten-3-one, O-methyl oxime.

Preferred methods of treatment are as defined herein using the abovenoted preferred, more preferred and most preferred compounds of theformula I and the compound1-(3,4-dihydroxyphenyl)-7-phenyl-1-hepten-3-one which compound ispreviously disclosed by Itokawa, et al as noted above but having nopreviously known pharmaceutical utility.

The present invention is also a pharmaceutical composition comprising aneffective amount of a compound having the formula I as defined abovetogether with a pharmaceutically acceptable carrier. An effective amountis the amount useful for treating or ameliorating a number of diseasesor conditions comprising an inhibition of a lipoxygenase effect. Thediseases or conditions are readily recognized for the pathogenesisaffected by the inhibitory lipoxygenase effect as recited herein.

Thus, in accordance with the present invention, another aspect of theinvention, provides a method of administering to mammals, includinghumans, in need of treatment or amelioration of diseases or conditionsan amount effective for treatment of the diseases or conditions of acompound or composition having the formula I as defined above. The needis evident for diseases or conditions benefiting from inhibition of alipoxygenase effect.

By virtue of the activity of the compounds having the formula I of thepresent invention as inhibitors of 5-lipoxygenase such compounds areuseful in treating asthmas and allergies as well as cardiovasculardisorders, migraine, and immunoinflammatory conditions as recited above.

The antiasthma and antiallergic activity provides methods of treatmentfor hypersensitivity reaction having broad symptoms. For example, thesymptoms may include dermatitis, lacrimation, nasal discharge, coughing,sneezing, nausea, vomiting, diarrhea, difficulty in breathing, pain,inflammation, and in severe cases, anaphylactic shock and circulatorycollapse. The symptoms may be found in man as well as other animalssuffering from bronchial asthma, seasonal pollinosis (e.g., hay fever),allergic rhinitis, urticaria, allergic conjunctivitis, food allergies,and anaphylactoid reactions.

Likewise, the activity of the compounds of formula I provides a methodof treatment for cardiovascular disorders, particularly ischemia andmyocardial infarctions. The symptoms of a subject having acardiovascular disorder may be determined by special diagnosticprocedures directed to subjects having a history, general physicalappearance and then detailed deviations from normal appearancessuggesting a cardiovascular disorder. Such disorders are also found inman as well as other mammals. Symptoms of the disorders are describedextensively in The Merck Manual 14th ed., (1982).

Further, method of treatment is provided by the compounds of formula Iherein for migraine, stroke and inflammation. The symptoms requiringtreatment for these purposes are also readily recognized, particularlyfor migraine in man and/or inflammation in man as well as other mammals.

The compounds of this invention are also useful as cytoprotectiveagents.

Pharmaceutical compositions which also are the present invention areprepared from the compound of formula I and salts thereof described asthe present invention having inert pharmaceutical carriers. Thecompositions may be either solid or liquid.

A physician or veterinarian of ordinary skill readily determines asubject who is exhibiting symptoms described herein. Regardless of theroute of administration selected, the compounds of the present inventionare formulated into pharmaceutically acceptable dosage forms byconventional methods known to the pharmaceutical art.

The compounds can be administered in such oral unit dosage forms such astablets, capsules, pills, powders, or granules. They also may beadministered rectally or vaginally in such forms as suppositories orbougies; they may also be introduced parenterally (e.g., subcutaneously,intravenously, or intramuscularly), using forms known to thepharmaceutical art. They are also introduced directly to an affectedarea (e.g., in the form of eye drops or by inhalation). For thetreatment of asthma or allergies such as erythema, and dermatologicaldisorders such as psoriasis and acne, the compounds of the presentinvention may also be administered topically in the form of ointments,creams, gels, or the like. However, in general, the preferred route ofadministration is orally.

An effective but nontoxic quantity of the compound is employed intreatment. The ordinarily skilled physician or veterinarian will readilydetermine and prescribe the effective amount of the compound to preventor arrest the progress of the condition for which treatment isadministered. In so proceeding, the physician or veterinarian couldemploy relatively low dosages at first, subsequently increasing the doseuntil a maximum response is obtained.

Initial dosages of the compounds of the invention having formula I areordinarily in the area of 10 mg up to 2 g per day orally, preferably 10mg to 500 mg per dose orally, given from one to four times daily or asneeded. When other forms of administration are employed equivalent dosesare administered.

The compounds of the invention are capable of forming bothpharmaceutically acceptable acid addition and/or base salts. Base saltsare formed with metals or amines, such as ammonium, alkali, and alkalineearth metals or organic amines. Examples of metals used as cations aresodium, potassium, magnesium, calcium, and the like. Examples ofsuitable amines are N,N'-dibenzylethylenediamine, chloroprocaine,choline, diethanolamine, ethylenediamine, N-methylflucamine, andprocaine.

Pharmaceutically acceptable acid addition salts are formed with organicand inorganic acids.

Examples of suitable acids for salt formation are hydrochloric,sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic,gluconic, fumaric, succinic, ascorbic, maleic, methanesulfonic,arginine, and the like. The salts are prepared by contacting the freebase form with a sufficient amount of the desired acid to produce eithera mono or di, etc. salt in the conventional manner. The free base formsmay be regenerated by treating the salt form with a base. For example,dilute solutions of aqueous base may be utilized. Dilute aqueous sodiumhydroxide, potassium carbonate, ammonia, and sodium bicarbonatesolutions are suitable for this purpose. The free base forms differ fromtheir respective salt forms somewhat in certain physical properties suchas solubility in polar solvents, but the salts are otherwise equivalentto their respective free base forms for purposes of the invention.

The compounds of the invention can exist in unsolvated as well assolvated forms, including hydrated forms. In general, the solvatedforms, including hydrated forms and the like are equivalent to theunsolvated forms for purposes of the invention.

Finally, the methods of preparation for compounds of formula I' are asgenerally as follows: ##STR24## wherein T, R₁, R₂ (except when R₂ is NR₃R₄), n, Y and Ar are as defined above.

A methyl ketone of formula II in a solvent, such as diethyl ether, orthe like is added to a mixture of pyrrolidine and acetic acid. Then, asolution of an analog of benzaldehyde having the formula III wherein Tand R₁ are as defined above and R₂ is as defined above (except when R₂is amino), in a solvent such as diethyl ether, tetrahydrofuran (THF),dimethoxyethane (DME) or the like is added dropwise and stirred at aboutroom temperature for about 12 to 48 hours to provide a condensationproduct of formula I' wherein T, R₁, n, Y and Ar are as defined aboveand R₂ is as defined above except when R₂ is amino.

When R₂ is amino as shown in a compound of formula IV a compound offormula I" is reduced by conventional methods using Raney Nickel toobtain the compound of formula IV wherein T, R, n, Y and Ar are asdefined above and R₂ is amino. The following Scheme II illustrates thisreduction. ##STR25## wherein T, R₁, n, Y and Ar are as defined above.

Alternatively, Scheme III illustrates a specific preparation for acompound of formula VI comprising a compound of formula III as definedabove and a phosphorane of the formula V wherein Y and Ar are as definedabove are dissolved in a solvent such as toluene, THF, dimethylsulfoxide(DMSO) or the like and warmed to reflux for from two to five hours,preferably three hours. The resulting product is treated intetrahydrofuran, ethylacetate (EtOAc), or the like with an excess ofsodium bisulfite dissolved in water. The treatment is at 0° to 25° C.preferably 25° C. for about one to three hours, preferably about onehour. The phosphorane of formula V is prepared in a manner analogous tothat described by Le Carre: C. R. Acad. Sci. Paris, 273, 81 (1971). Thisalternative process is shown in Scheme III as follows: ##STR26## whereinT, R₁, n, Y and Ar are as defined above and R₂ is as defined aboveexcept R₂ is not the amino group.

Finally, the compounds of formula VII are prepared as shown in thefollowing Scheme IV in which a compound of formula I', IV or VI havingthe definitions noted above are dissolved in a solvent such as methanol,ethanol, iso-propanol or the like. Hydroxyamine and sodium acetate areadded to the solution and the resulting solution stirred for two hoursat about room temperature giving the compound of formula VII. ##STR27##wherein T, R₁, R₂, n, Y and Ar are as defined above.

Compounds of formula I wherein Z is sulfur can be prepared by usingmethods analogous to those known in the art. Likewise, compounds whereinX is (CH₂)_(n) can be prepared using appropriate alkenylene containingcompounds of formula I which are then hydrogenated by conventionalmethods. One of skill in the art would recognize variations in thesequence which may be appropriately used in the processes to make thecompounds of formula I herein.

Under certain circumstances it is necessary to protect either the N or 0of intermediates in the above noted process with suitable protectinggroups which are known. Introduction and removal of such suitable oxygenand nitrogen protecting groups are well-known in the art of organicchemistry; see for example "Protective Groups in Organic Chemistry," J.F. W. McOmie, ed., (New York, 1973), pages 43ff, 95ff, J. F. W. McOmie,Advances in Organic Chemistry, Vol. 3, 191-281 (1963); R. A. Borssonas,Advances in Organic Chemistry, Vol. 3, 159-190 (1963); and J. F. W.McOmie, Chem. & Ind., 603 (1979).

Examples of suitable oxygen protecting groups are benzyl,t-butyldimethylsilyl, ethoxyethyl, and the like. Protection of an N-Hcontaining moiety is necessary for some of the processes describedherein for the preparation of compounds of this invention. Suitablenitrogen protecting groups are benzyl, triphenylmethyl, trialkylsilyl,trichloroethylcarbamate, trichloroethoxycarbonyl, vinyloxycarbamate, andthe like.

Under certain circumstances it is necessary to protect two differentoxygens with dissimilar protecting groups such that one can beselectively removed while leaving the other in place. The benzyl andt-butyldimethylsilyl groups are used in this way; either is removable inthe presence of the other, benzyl being removed by catalytichydrogenolysis, and t-butyldimethylsilyl being removed by reaction with,for example, tetra-n-butylammonium fluoride.

In the process described herein for the preparation of compounds of thisinvention the requirements for protective groups are generally wellrecognized by one skilled in the art of organic chemistry, andaccordingly the use of appropriate protecting groups is necessarilyimplied by the processes of the charts herein, although not expresslyillustrated.

The products of the reactions described herein are isolated byconventional means such as extraction, distillation, chromatography, andthe like.

The salts of compounds of formula I described above are prepared byreacting the appropriate base or acid with a stoichiometric equivalentof the compounds of formula I, respectively, to obtain pharmaceuticallyacceptable salts thereof.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention is further elaborated by the representative examples asfollows. Such examples are not meant to be limiting.

EXAMPLE 1 1-(3-Hydroxy-4-methoxyphenyl)-7-phenyl-1-hepten-3-one

Pyrrolidine (2.42 g, 34.0 mMol) is added to acetic acid (2.04 g, 34.0mMol), and the mixture is stirred at room temperature for 20 minutes.After this time, 6-phenyl-2-hexanone (4.00 g, 22.6 mMol) as a solutionin diethyl ether (20 ml) is added, and the mixture is allowed to stirfor an additional 15 minutes. An ethereal solution of iso-vanillin (3.45g, 22.5 mMol) is then added dropwise. The reaction mixture is stirredfor 48 hours. HCl (1.0 N, 30 ml) is then added to the reaction mixture,and the contents stirred for 20 minutes. The mixture is then taken upinto an equal volume of ethyl acetate, and the phases separated. Theorganic layer is washed with saturated aqueous sodium bicarbonate, dried(sodium sulfate), and concentrated. The residue is chromatographed(silica gel; hexane/ethyl acetate 3:1) to afford 1.0 g (28%) of1-(3-hydroxy-4-methoxy-phenyl)-7-phenyl-1-hepten-3-one, mp=70°14 75° C.C, H analysis: Calcd. for C₂₀ H₂₂ O₃ (77.39, 7.14); Found (77.68, 6.94).The procedure of Example 1 is within that described in the above citedreference by Itokawa H. et al in the Chem. Pharm. Bull. Similarlyprepared are Examples 2-12 using the procedure of Example 1.

                  TABLE 1                                                         ______________________________________                                         ##STR28##                                                                                                        Elemental                                                                     Analysis                                                         Yield        C, H, N (Calcd)                           Example                                                                              R.sub.1, R.sub.2                                                                        n     (%)   mp (°C.)                                                                      C, H, N (Found)                           ______________________________________                                         2*    3,4-(OH).sub.2                                                                          4     20    110-115                                                                              77.00, 6.80                                                                   77.20, 6.71                                3*    4-OH      4     28    82-85  80.81, 7.85                                                                   81.20, 7.78                               4      3-CH.sub.2 OH,                                                                          4     30    65-68  77.98, 6.04                                      4-OH                         78.27, 6.16                               5      3-Cl, 4-OH                                                                              4     45    72-74  72.49, 6.08                                                                   72.42, 6.21                               6      4-COOH    4           160-162                                                                              71.20, 5.27                                                                   71.40, 5.32                                7*    3-OMe,    3     29    (Oil)  75.85, 6.87                                      4-OH                         75.79, 7.00                                8*    3,4-(OH).sub.2                                                                          3     51    141-145                                                                              76.57, 6.42                                                                   75.84, 6.75                                 9*   3-OMe,    2     50    70-76  71.55, 6.73                                      4-OH                         71.38, 6.45                               10     3-CH.sub.2 OH,                                                                          2     54    122-128                                                                              76.57, 6.42                                      4-OH                         76.38, 6.51                               11     3-Cl, 4-OH                                                                              2     40    128-132                                                                              71.20, 5.27                                                                   71.40, 5.32                               12     3-NO.sub.2,                                                                             2     56    115-118                                                                              68.68, 5.08, 4.71                                4-OH                         68.37, 5.22, 4.67                         ______________________________________                                         *See Itokawa, H. et al, "Synthesis of Diarylheptanoids and Assessment of      Their Pungency," Chem. Pharm. Bull., 31, 2491 (1983).                    

EXAMPLE 13 1-Penten-3-one, 1,5-bis(4-hydroxy-3-methoxyphenyl)

1,5-bis(4-hydroxy-3-methoxyphenyl)-1-penten-3-one is prepared accordingto the procedure of Example 1 from vanillin and3-methoxy-4-hydroxybenzylacetone in 45% yield. C, H analysis: Calcd forC₁₉ H₂₀ O₅ (69.50, 6.13); Found (69.52, 6.15).

EXAMPLE 14 1-(4-Hydroxy-3-methoxyphenyl)-6-phenoxy-1-hexene-3-one

According to the procedure of Example 1,1-(4-hydroxy-3-methoxyphenyl)-6-phenoxy-1-hexene-3-one is prepared fromvanillin and 5-phenoxy-2-pentanone in 40% yield, mp=67°-70° C. C, Hanalysis: Calcd for C₁₉ H₂₀ O₄ ·0.1H₂ O (72.67, 6.50); Found (72.48,6.49).

EXAMPLE 14A

Following to the procedure of Example 1, and using appropriate startingmaterials in THF or THF and DMF mixture as solvent, the followingcompounds are prepared and purified by extensive chromatography toseparate it from other isomeric products.

    __________________________________________________________________________                Yield                                                             Example                                                                            R.sub.1, R.sub.2                                                                     (%) mp   Anal % C % H                                                                              % Br                                         __________________________________________________________________________    14A  3-MeO, 5-Br                                                                          20.8                                                                              114-118                                                                            C, H, Br                                                                           59.85,                                                                            4.74,                                                                            22.12                                                                  59.67,                                                                            4.75,                                                                            22.08                                        14A  3,5-(MeO).sub.2                                                                      18.5                                                                              93-94                                                                              C, H 73.06,                                                                            6.45                                                                             --                                                                     72.89,                                                                            6.48                                                                             --                                           14A  3,5-Me.sub.2                                                                         12.0                                                                              104-105                                                                            C, H 81.39,                                                                            7.19                                                                             --                                                                     81.85;                                                                            7.26;                                                                            --                                                                     81.73                                                                             7.36                                            __________________________________________________________________________

EXAMPLE 15 [1-Pentene-3-one, 1-(3-amino-4-hydroxyphenyl)-5-phenyl]

1-Pentene-3-one, 1-(4-hydroxy-3-nitrophenyl)-5-phenyl (3.0 g, 1.0×10⁻²moles) is reduced to the product in THF (100 ml) in the presence ofRaney Nickel (0.2 g) under a pressure of 15 psi. The crude reactionmixture is evaporated to dryness and chromatographed on a flash columnusing hexane:ethyl acetate 3:1 to give 2.6 g of 1-pentene-3-one,1-(3-amino-4-hydroxyphenyl)-5-phenyl (99% yield), mp=154°-158° C. C, H,N analysis calculated with 0.2 m H₂ O C, H, N (75.36, 6.47, 5.19); C, H,N Found (75.36, 6.56, 5.19).

EXAMPLE 16 1-(4'-Hydroxy-3'-methoxyphenyl)-4-phenoxy-1-butene-3-one

4-Hydroxy-3-methoxybenzaldehyde (2.1 g, 13.8 mMol) and3-phenoxypropane-2-one triphenylphosphorane (2.8 g, 6.9 mMol) (preparedas described by LeCorre: C. R. Acad. Sci. Paris, 273 81 (1971)) aredissolved in 100 ml of toluene and warmed to reflux. After three hours,the solvent is evaporated and the residue is taken up in tHF. Sodiumbisulfite (10.0 g) is dissolved in 100 ml of water and stirred with thesolution for one hour. The THF is evaporated and the water is extractedwith chloroform. Drying over magnesium sulfate and evaporation of thechloroform gives a yellow oil. Flash chromatography in ethyl acetate onsilica gel gives 1.5 g (65%) of1-(4'-hydroxy,3'-methoxyphenyl)-4-phenoxy-1-butene-3-one; mp=85°-87° C.C, H analysis: Calcd for C₁₇ H₁₆ O₄ (71.81, 5.68); Found (71.85, 5.50).

EXAMPLE 16A 2-Oxo-3-(phenylthio)propylidene triphenylphosphorane

Prepared by the method of Banerjee (Prostaglandins, 22, 167-182 (1981)).Yield=50%; mp=133°-135° C.

1-(4-Hydroxy-3-methoxyphenyl)-4-phenylthio-1-butene-3-one

Prepared by the method of Example 16. Flash chromatography in methylenechloride gives 1.3 g (62%) of1-(4-hydroxy-3-methoxyphenyl)-4-phenylthio-1-butene-3-one; mp=78°-80° C.Analysis for C₁₇ H₁₆ O₃ S requires C-67.97, H-5.38. Found: C-67.88,H-5.31.

EXAMPLE 17 1-Hepten-3-one, 1-(4-hydroxy-3-methoxyphenyl)-7-phenyl, oxime

1-Hepten-3-one, 1-(4-hydroxy-3-methoxyphenyl)-7-phenyl (Ref. H. Itokawa,Chem. Pharm. Bull., 31, 2491 (1983) and as prepared in Example 1 above)(1.50 g, 4.80 mMol) is dissolved in methanol (130 ml) and stirred withhydroxylamine·HCl (2.0 g, 29.0 mMol) and sodium acetate (2.40 g, 29.0mMol) for two hours at room temperature. The mixture is then evaporatedto dryness, redissolved in ethyl acetate (100 ml), and washed withwater. The organic layer is then dried (sodium sulfate) andconcentrated. Chromatography (silica gel, hexane:ethyl acetate, 3:1)affords a quantitative yield of 1-hepten-3-one,1-(4-hydroxy-3-methoxyphenyl)-7-phenyl-, oxime; mp=115°-118° C. C, H, Nanalysis: Calcd for C₂₀ H₃₃ NO₃ (73.82, 7.12, 4.30); Found (74.04, 7.12,4.39).

Following the procedure of Example 17, and using the appropriatestarting materials as prepared above or as prepared by analogousmethods, the following oximes of Table 2 are prepared.

                  TABLE 2                                                         ______________________________________                                         ##STR29##                                                                                                        Elemental                                                                     Analysis                                                         Yield        C, H, N (Calcd)                           Example                                                                              R.sub.1, R.sub.2                                                                        n     (%)   mp (°C.)                                                                      C, H, N (Found)                           ______________________________________                                        18     3-OH,     4     100    95-105                                                                              73.82, 7.12, 4.30                                4-OMe                        74.06, 7.26, 4.03                         19     3,4-(OH).sub.2                                                                          4     100   137-140                                                                              73.29, 6.80, 4.50                                                             73.19, 6.87, 4.60                         20     3-CH.sub.2 OH,                                                                          4     100   135-138                                                                              73.82, 7.12, 4.30                                4-OH                         73.51, 7.53, 4.23                         21     3-OMe,    2     100   (Oil)  71.79, 6.50, 4.65                                4-OH                         71.79, 6.63, 4.73                         22     3-CH.sub.2 OH                                                                           2     100   155-158                                                                              72.71, 6.44, 4.71                                                             72.39, 6.58, 4.77                         23     3-NH.sub.2,                                                                             2     100   143-147                                                                              73.32, 6.42, 9.92                                4-OH                         72.91, 6.54, 9.64                         ______________________________________                                    

EXAMPLE 24 1-(4-Hydroxy-3-methoxyphenyl)-4-phenoxy-1-buten-3-one oxime.

Following the procedure of Example 17,1-(4-hydroxy-3-methoxyphenyl)-4-phenoxy-1-buten- 3-one oxime is preparedin 39% yield; mp=155°-158° C. C, H, N analysis: Calcd for C₁₇ H₁₇ NO₄(68.20, 5.74, 4.68); Found (68.26, 6.02, 4.92).

EXAMPLE 24A

1-(4-Hydroxy-3-methoxyphenyl)-4-phenylthio-1-buten-3-one oxime

Following the procedure of Example 17,1-(4-hydroxy-3-methoxyphenyl)-4-phenylthio-1-butene-3-one oxime isprepared in 28% yield; mp=90°-100° C. C, H, N analysis: Calcd for C₁₇H₁₇ NO₃ S (64.73, 5.44, 4.44); Found (64.44, 5.48, 4.37).

EXAMPLE 25 1-(4-Hydroxy-3-methoxyphenyl)-6-phenoxy-1-hexen-3-one oxime.

Following the procedure of Example 17,1-(4-hydroxy-3-methoxyphenyl)-6-phenoxy-1-hexen-3-one is prepared in 76%yield. C, H, N analysis: Calcd for C₁₉ H₂₁ NO₄ ·H₂ O (66.06, 6.72,4.06); Found (66.28, 6.80, 4.39).

EXAMPLE 26 1-(4-Hydroxy-3-methoxyphenyl)-7-phenyl-1-hepten-3-one,O-methyl oxime.

A mixture of 1-(4-hydroxy-3-methoxyphenyl)-7-phenyl-1-hepten-3-one (0.50g, 1.61 mMol), methoxylamine·HCl (0.403 g, 4.83 mMol), and sodiumacetate (0.396 g, 4.83 mMol) is stirred in methanol (10 ml) at roomtemperature for 12 hours. The mixture is then concentrated and taken upinto chloroform. The organic layer is washed with water and brine, andthen dried (sodium sulfate). Concentration gives pure1-(4-hydroxy-3-methoxyphenyl)-7-phenyl-1-hepten-3-one, O-methyl oxime(490 mg) as a semi-solid.

EXAMPLE 27 1-(3-Methoxy-4-hydroxyphenyl)-5-(2-furyl)-1-penten-3-one

Using the method of Example 1 using 1-(2-furyl)-3-butanone bp 75°-78° C.at 10 mm Hg (prepared by the method analogous to Yamashita, Tet. Let.,1975, p. 1867 with a yield of 47%) the1-(3-methoxy-4-hydroxyphenyl)-5-(2-furyl) -1-pentene-3-one is preparedin 49% yield. mp=82°-84° C. C, H, N analysis: Calcd for C₁₆ H₁₆ O₄(70.56, 5.93); Found (70.50, 6.14).

EXAMPLE 28 1-(3-Methoxy-4-hydroxyphenyl)-5-(2-furyl)-1-penten-3-oneoxime

Using the procedure of Example 17, 1-(3-methoxy-4-hydroxyphenyl)-5-(2-furyl)-1-pentene-3-one oxime is prepared in 61% yield;mp=110°-120° C. C, H, N analysis: Calcd for C₁₆ H₁₇ NO₄ (66.88, 5.98,4.88); Found (66.57, 6.03, 4.80).

EXAMPLE 28A(E,E)-1-(4-Hydroxy-3,5-dimethoxyphenyl)-5-phenyl-1-penten-3-one oxime(Isomer A) and(Z,E)-1-(4-hydroxy-3,5-dimethoxyphenyl-5-phenyl-1-penten-3-one oximeIsomer B)

A mixture of(E)-1-(4-hydroxy-3,5-dimethoxyphenoxyphenyl)-5-phenyl-1-penten-3-one(2.5 g; 8.0 mmol), hydroxylamine hydrochloride (1.84 g; 26.0 mmol) andanhydrous sodium acetate (2.17 g; 26.0 mmol) in MeOH (100 ml is stirredat 24° C. for 18 h. The reaction mixture is evaporated to dryness andthe residue decomposed with water and extracted with CH₂ Cl₂. The CH₂Cl₂ extract is evaporated to dryness to give an oil (3.0 g) which isflash chromatographed over silica gel (90 g; 230-400 mesh) using CHCl₃and increasing amount of ethyl acetate as eluents. Elution with 5% ethylacetate-CHCl₃ gives the faster moving product, isomer A, as a singleisomer. It is recrystallized from isopropyl ether to give whitecrystalline solid. Yield 110 mg (4.2%), mp 144°-146° C. TLC (SiO₂, CHCl₃-AcOEt (3:1)) gives an Rf value of 0.42. It is assigned thestereochemistry of E,E-.

Further elution with 5% AcOEt-CHC₃ gives fractions which containmixtures of isomer A and isomer B as crude solid which is recrystallizedfrom isopropyl ether as white solid. Yield 1.13 g (43%), mp 110°-117° C.TLC (SiO₂, CHC₃ -AcOEt (3:1) gives two spots for isomer A and isomer Bwith Rf values of 0.42 and 0.33, respectively.

Elution with 10% AcOEt-CHC₃ gives isomer B as single product which isrecrystallized from isopropyl ether. Yield 0.64 g (24.4%), mp 120°-124°C. TLC (SiO₂, CHC₃ -AcOEt (3:1)) shows it as one spot with Rf value of0.33. It is assigned the stereochemistry E,Z-.

EXAMPLE 28B

Following the procedure of Example 28A above, the following compoundsare synthesized as a mixture of E,E- and E,Z- isomers.

(E,E-)-1(4-Hydroxy-3,5-dimethylphenyl)-5-phenyl-1-penten-3-one oxime and(Z,E)-1-(r-hydroxy-3,5-dimethylphenyl)-5-phenyl-1-penten-3-one oximemixture

Yield 0.76 g (51.5%), mp 110°-124° C. TLC shows two close spots (SiO₂,CHC₃,-AcOEt, (3:1)) with Rf values of 0.557 and 0.489 consistent withthe structure of the title compound.

EXAMPLE 28C

Following the procedure of Example 14A, the thienyl and furanylpentenones (where R=O) are prepared. The corresponding oximes areprepared following the procedure of Example 28A or Example 28B. Thefollowing examples are prepared as shown in Table 1 as follows.

                                      TABLE 3                                     __________________________________________________________________________     ##STR30##                                                                    Ex-                                                                           am-                        Yield                                                                              Purifica-   Analysis                          ple                        Purified                                                                           tion Empirical                                                                            C   H   N   Br  S                 No.                                                                              Q Z   T   R.sub.2                                                                           Q.sub.1                                                                            MP °C.                                                                      % (g)                                                                              Solvent                                                                            Formula                                                                              Calcd/Found                       __________________________________________________________________________    28C1                                                                             O O   OCH.sub.3                                                                         OCH.sub.3                                                                         H    107-109                                                                            9(1.4)                                                                             Methyl-                                                                            C.sub.17 H.sub.18 O.sub.5                                                            67.54,                                                                            6.0                                                           ene         67.25,                                                                            6.14                                                          chloride                                                                      isopropyl                                                                     ether                                         28C2                                                                             O O   OCH.sub.3                                                                         Br  H    106-107                                                                            14(1.51)                                                                           Methanol                                                                           C.sub.16 H.sub.15 BrO.sub.4                                                          54.72,                                                                            4.31,   22.75                                                             54.64,                                                                            4.31,   22.99                 28C3                                                                             O NOH OCH.sub.3                                                                         OCH.sub.3                                                                         H    650  72(1.5)   C.sub.17 H.sub.19 NO.sub.5                                                           64.34,                                                                            6.04,                                                                             4.41                                                                  63.96,                                                                            6.15,                                                                             4.22                      28C4                                                                             S O   OCH.sub.3                                                                         H   H    75-77                                                                              38.5(7.2)                                                                          Ethyl                                                                              C.sub.16 H.sub.16 O.sub.3 S                                                          66.64,                                                                            5.59,       11.12                                             acetate-    66.83,                                                                            5.53,       11.15                                             hexane                                        28C5                                                                             S O   OCH.sub.3                                                                         OCH.sub.3                                                                         H    117-119                                                                            46(7.4)                                                                            Ethyl                                                                              C.sub.17 H.sub.18 O.sub.4 S                                                          64.13,                                                                            5.70,       10.07                                             acetate                                                                            64.02, 5.67,                                                                             9.69                          28C6                                                                             S NOH OCH.sub.3                                                                         H   H    104-110                                                                            57.4(2.9)                                                                          Ethyl                                                                              C.sub.16 H.sub.17 NO.sub.3 S                                                         63.34,                                                                            5.65,                                                                             4.62                                                      acetate-    63.12,                                                                            5.48,                                                                             4.53                                                      hexane                                        28C7                                                                             S NOH OCH.sub.3                                                                         OCH.sub.3                                                                         H    67-70                                                                              51(2.7)                                                                            Ethyl                                                                              C.sub.17 H.sub.19 NO.sub.4 S                                                         61.24,                                                                            5.74,                                                                             4.20,   9.62                                              acetate-    61.20,                                                                            5.64,                                                                             4.06,   9.77                                              hexane                                        28C8                                                                             S O   CH.sub.3                                                                          CH.sub.3                                                                          H    118-120                                                                            39(4.6)                                                                            Ethyl                                                                              C.sub.17 H.sub.18 O.sub.2 S                                                          71.30,                                                                            6.33                                                          acetate-    71.32,                                                                            6.34                                                          hexane                                        28C9                                                                             O O   CH.sub.3                                                                          CH.sub.3                                                                          H    142-144                                                                            39.2 Toluene                                                                            C.sub.17 H.sub.18 O.sub.3                                                            75.53,                                                                            6.71                                                     (10.59)          75.62,                                                                            6.66                          28C10                                                                            S NOH CH.sub.3                                                                          CH.sub.3                                                                          H    123-130                                                                            65(2.3)                                                                            Ethyl                                                                              C.sub.17 H.sub.19 NO.sub.2 S                                                         67.74,                                                                            6.35,                                                                             4.65,   10.64                                             acetate-    67.95,                                                                            6.30,                                                                             4.81,   10.98                                             hexane                                        28C11                                                                            O NOH CH.sub.3                                                                          CH.sub.3                                                                          H    112-114                                                                            58.2(3.8)                                                                          Ethyl                                                                              C.sub.17 H.sub.19 NO.sub.3                                                           71.56,                                                                            6.71,                                                                             4.91                                                      acetate-    71.47,                                                                            6.86,                                                                             5.03                                                      hexane                                        28C12                                                                            O O   +   H   H    117-119                                                                            33.7(4.41)                                                                         Ethyl                                                                              C.sub.19 H.sub.22 O.sub.3                                                            76.48,                                                                            7.43                                                          acetate-    76.32,                                                                            7.40                                                          hexane                                        28C13                                                                            O NOH +   H   H    65-87                                                                              17.3(0.6)                                                                          Ethyl                                                                              C.sub.19 H.sub.23 NO.sub.3                                                           72.82,                                                                            7.40,                                                                             4.47                                                      ether-      72.63,                                                                            7.41,                                                                             4.52                                                      hexane                                        28C14                                                                            O O   OCH.sub.3                                                                         +   H    115-117                                                                            34.1(2.15)                                                                         Ethyl                                                                              C.sub.2024 O.sub.4                                                                   73.14,                                                                            7.37                                                          ether-      73.11,                                                                            7.60                                                          hexane                                        28C15                                                                            O O   OCH.sub.3                                                                         Br  CO.sub.2 CH.sub.3                                                                  112-123                                                                            40(24.6)                                                                           Methanol                                                                           C.sub.18 H.sub.17 BrO.sub.6                                                          52.76,                                                                            3.92,   19.49                 28C16                                                                            O O   +   H   CO.sub.2 CH.sub.3                                                                  183-185                                                                            42.8(6.8)                                                                          Methanol                                                                           C.sub.21 H.sub.24 O.sub.5                                                            70.76,                                                                            6.79                                                                      70.54,                                                                            6.67                          __________________________________________________________________________

The starting benzaldehydes are prepared according to the followingliterature references.

3-tert-Butyl-5-hydroxybenzaldehyde and3-Bromo-5-tert-butyl-4-hydroxybenzaldehyde, Ikuo Katsume et al. Chem.Pharm. Bull., 1986, 34(1), 121-129.

3-tert-Butyl-5-methoxy-4-hydroxybenzaldehyde, H. Hemetsberger and D.Knittel. Monatsheften fur chemie, 1971. 102, 1110-1119.

3-tert-Butyl-5-methyl-4-hydroxybenzaldehyde, S. L. Shapiro et al. J.Org. Chem., 1961, 26, 3580.

EXAMPLE 28D(E)-5-[5-[4-Hydroxy-3-methoxyphenyl)-3-oxo-4-pentenyl]-2-furancarboxylicacid, methyl ester.

According to the procedure of Example 14A,(E)-5-[5-(4-hydroxy-3-methoxy-phenyl)-3-oxo-4-pentenyl]-2-F-urancarboxylicacid, methyl ester is prepared frommethyl-4-(2-furanyl)-2-butan-one-5-carboxylate (S. M. Singh, Indian J.Chem. Sect. B, 1979, 18B(4), 363-5) and vanillin. Recrystallization fromethyl acetate-hexane gives 14.6 g (29.5%) of analytically pure product,mp 93°-94° C. C, H analysis: Calculated for C₁₈ H₁₈ O₆ (65.44. 5 49);Found (65.31, 5.52).

EXAMPLE 28E

5-[5-(4-hydroxy-3-methoxyphenyl)-3-(hydroxyimino)-4-pentenyl]-2-furancarboxylicacid, methyl ester is prepared by the method of Example 17. Purificationby flash chromatography (silica gel, chloroform: ethyl acetate 95:5 aseluent), afforded a white solid, which after recrystallization fromether-hexane gives 6.4 g (72%) of analytically pure product, mp110°-125° C. C, H, N analysis: Calculated for C₁₈ H₁₉ NO₆ (62.60, 5.55,4.06); Found 62.76, 5.54, 3.90).

EXAMPLE 28F(E)-5[3-(Hydroxyimino)-5-(4-hydroxy-3-methoxyphenyl)-4-pentenyl)-2-furancarboxylicacid.

A mixture of5-[5-(4-hydroxy-3-methoxyphenyl)-3-hydroxyimino)-4-pentenyl]-2-furancarboxylicacid, methyl ester (4.4 g, 0.0127 mole), potassium hydroxide (4.2 g) andmethanol (200 ml) is refluxed for four hours. Most of the methanol isremoved under reduced pressure, <35° C. The residue is dissolved inwater. After cooling, the basic solution is carefully acidified withdilute hydrochloric acid and extracted with ether. Drying over sodiumsulfate and evaporation of the ether gives 3.9 g of a solid, mp103°-110° C. Recrystallization from ethyl acetate-hexane gives 0.5 g(11.9%) of(E)-5-[3-(hydroxyimino)-5-(4-hydroxy-3-methoxyphenyl)-4-pentenyl]-2-furancarboxylicacid, mp 187°-189° C. (dec.). C, H, N analysis: Calculated for C₁₇ H₁₇NO₆ (61.33, 5.17, 4.23); Found (61.35, 5.11, 4.04).

EXAMPLE 28G(E,E)-1-(3-Bromo-4-hydroxy-5-methoxyphenyl)-5-(2-furanyl)-1-penten-3-one,oxime

1-(3-Bromo-4-hydroxy-5-methoxyphenyl)-5-(2-furanyl)-1-pentene-3-one asprepared in Example 2 of Table 1 (9.2 g, 0.026 mole) is dissolved inmethanol (500 ml) and stirred with hydroxylamine HCl (6.05 g, 0.087mole) and sodium acetate (7.14 g, 0.087 mole) for 48 hours at roomtemperature. The mixture is then evaporated to dryness, redissolved inmethylene chloride, and washed with water. The organic layer is thendried over sodium sulfate and concentrated to give quantitative yield ofoxime (9.5 g), as an oil. Purification by flash chromatography (silicagel, chloroform:methanol 95:5 as eluent) then rechromatography usingchloroform:ethyl acetate 95:5 as eluent gives 1.0 g of pure compound, mp133°-135° C. Recrystallization from ether-hexane gives 0.7 g (7%) of(E,E)-1-(3-bromo-4-hydroxy-5-methoxyphenyl)-5-(2-furanyl)-1-penten-3-one,oxime, mp 133°-135° C. C, H, N, Br analysis: Calculated for C₁₆ H₁₆BrNO₄, 52,48, 4.40, 3.38, 21.82); Found (52.55, 4.20), 3.53, 21.78).

EXAMPLE 28H(Z,E)-1-(3-Bromo-4-hydroxy-5-methoxyphenyl)-5-(2-furanyl)-1-pentene-3-one-oxime

Further elution of the column from Example 28G with chloroform:methanol9:1, gives an oil, which after recrystallization from ether-hexane gives3.2 g (34%) of(Z,E)-1-(3-bromo-4-hydroxy-5-methoxyphenyl)-5-(2-furanyl)-1-penten-3-one,oxime, mp 58°-110° C. (a mixture consisting of 75% Z,E and 25% E,Eisomer by NMR. C, H, N, Br analysis: Calculated for C₁₆ H₁₆ BrNO₄(52.48, 4.40, 3.38); Found (52.45; 4.28; 3.52).

EXAMPLE 29α-((4-Hydroxy-3,5-dimethoxyphenyl)methylidine)-β-oxo-5-(2-furan)pentanoic¹acid, ethyl ester, Method 1.

A mixture of ethyl 5-(2-furanyl)-3-oxopentanoate¹ (157.48 g, 0.75 mol),syringic aldehyde (91.0 g, 0.5 mol), 4-methyl piperidine (4.0 g, 0.04mol), and benzoic acid (0.97 g, 0.0078 mol) in toluene (600 ml) isheated to reflux under nitrogen for 24 hours with a water separator. Themixture is cooled, diluted with ether (1.0 L) and washed successivelywith 5% HCl, water, NaHCO₃ solution, water, 5% acetic acid and and thendried (Na₂ SO₄). The solvent is removed under reduced pressure and thecrude oil (212 g) is chromatographed over silica gel. Elution withmethylene chloride gives the crude product as solid which isrecrystallized from ether. Yield 70.7 g (37.8%), mp 103°-104° C.

EXAMPLE 29α-[4-Hydroxy-3,5-dimethoxyphenyl)methylene]-β-oxo-5-2-furan)pentanoicacid, ethyl ester, Method 2

A mixture of ethyl-3-oxo-5(2-furyl)-pentanoate¹ (31.5 g, 0.15 mole),syringic aldehyde (182. g, 0.1 mole) piperidine (12 ml), acetic acid (12ml) in toluene (500 ml) is refluxed under nitrogen for 24 hours. Wateris collected with a Dean-Stark trap. The mixture is cooled and washedsuccessively with 5% hydrochloric acid, water, sodium bicarbonatesolution, and water. The extract is dried over sodium sulfate and thesolvent is removed under reduced pressure. The crude oil ischromatographed on silica gel column. Elution with chloroform:methanol95:5, gives after recrystallization from isopropyl ether 2.8 g (7.5%) ofα-[(4-hydroxy-3,5-dimethoxyphenyl)methylene]-β-oxo-5-(2-furan)pentanoicacid, ethyl ester, mp 103°-104° C. C, H analysis: Calculated for C₂₀ H₂₂O₇ (64.16, 5.92); Found (64.44, 5.85).

                                      TABLE 4                                     __________________________________________________________________________     ##STR31##                                                                    Ex-                                         Analysis                          ample              Yield                                                                             Condensing                                                                            Purification                                                                        Empirical                                                                            C   H  N Cl Br  S                 No. Q T   R.sub.2                                                                           MP °C.                                                                      % (g)                                                                             Agent   Solvent                                                                             Formula                                                                              Calcd/Found                       __________________________________________________________________________    29A1                                                                              O +   +   80-82                                                                              9.4 Piperidine,                                                                           Hexane                                                                              C.sub.26 H.sub.16 Br.sub.2 O.sub.5                                                   73.21,                                                                            8.04                                             (8) benzoic              73.19,                                                                            8.04                                                 acid                                                   29A2                                                                              O Br  Br  74-82                                                                              48  4-Methyl-                                                                             Isopropyl                                                                           C.sub.18 H.sub.16 Br.sub.2 OS                                                        45.79,                                                                            3.42,   33.85                                    (13.6)                                                                            piperidine,                                                                           ether-       45.77,                                                                            3.28,   34.15                                        acetic acid,                                                                          hexane                                                                benzoic acid                                           29A3                                                                              O OCH.sub.3                                                                         Br  97-99                                                                              21.2                                                                              4-Methyl-                                                                             Methylene                                                                           C.sub.19 H.sub.19 BrO.sub.6                                                          53.91,                                                                            4.52,   18.88                                    (8.95)                                                                            piperidine,                                                                           chloride-    53.67,                                                                            4.37    18.58                                        benzoic acid                                                                          hexane                                         29A4                                                                              O OCH.sub.3                                                                         H   123-125                                                                            19  4-Methyl-                                                                             Ethyl C.sub.19 H.sub.20 O.sub.6                                                            66.27,                                                                            5.85                                             (2.6)                                                                             piperidine,                                                                           acetate      66.43,                                                                            5.72                                                 benzoic acid                                           29A5                                                                              O Cl  Cl  72-79                                                                              23.7                                                                              4-Methyl-                                                                             Methylene                                                                           C.sub.18 H.sub.16 Cl.sub.2 O.sub.5                                                   56.41,                                                                            4.21,                                                                              18.50                                       (2.2)                                                                             piperidine,                                                                           chloride-    56.56,                                                                            4.22,                                                                              18.71                                           acetic acid,                                                                          hexane                                                                benzoic acid                                           29A6                                                                              O +   H   107-109                                                                            9.5 4-Methyl-                                                                             Diethyl                                                                             C.sub.22 H.sub.26 O.sub.5                                                            71.33,                                                                            7.08                                             (1.4)                                                                             piperidine,                                                                           ether-       71.42,                                                                            7.03                                                 benzoic acid                                                                          isopropyl                                                                     ether                                          29A7                                                                              S CH.sub.3                                                                          CH.sub.3                                                                          120-122                                                                            28.5                                                                              4-Methyl-                                                                             Methylene                                                                           C.sub.20 H.sub.22 O.sub.4                                                            67.01,                                                                            6.80                                             (10.2)                                                                            piperidine,                                                                           chloride-    67.02,                                                                            6.00                                                 piperidine,                                                                           toluene                                                               benzoic acid                                           29A8                                                                              O CH.sub.3                                                                          CH.sub.3                                                                          99-101                                                                             38.6                                                                              4-Methyl-                                                                             Toluene                                                                             C.sub.20 H.sub.22 O.sub.5                                                            70.16,                                                                            6.48                                             (13.2)                                                                            piperidine,          70.40,                                                                            6.34                                                 piperidine,                                                                   benzoic acid                                           29A9                                                                              O CH.sub.3                                                                          +   88-90                                                                              24  4-Methyl-                                                                             Diethyl                                                                             C.sub.23 H.sub.28 O.sub.5                                                            71.85,                                                                            7.34                                             (2.4)                                                                             piperidine,                                                                           ether-       71.89,                                                                            7.25                                                 piperidine                                                                            hexane                                                                benzoic acid,                                                                 acetic acid                                            29A10                                                                             S +   +   90-92                                                                              4.3 4-Methyl-                                                                             Toluene-                                                                            C.sub.26 H.sub.34 O.sub.4 S                                                          70.56,                                                                            7.74,       7.24                                 (1.9)                                                                             piperidine,                                                                           hexane       70.93,                                                                            7.90,       7.20                                     benzoic acid                                           29A11                                                                             O +   Br  88-91                                                                              31.5                                                                              4-Methyl-                                                                             Diethyl                                                                             C.sub.22 H.sub.25 BrO.sub.5                                                          58.81,                                                                            5.61,   17.78                                    (2.2)                                                                             piperidine,                                                                           ether-       58.78,                                                                            5.60    17.48                                        piperidine,                                                                           hexane                                                                benzoic acid                                           29A12                                                                             S OCH.sub.3                                                                         OCH.sub.3                                                                         93-94                                                                              6.2 4-Methyl-                                                                             Ethanol-                                                                            C.sub.20 H.sub.22 O.sub.6 S                                                          61.52,                                                                            5.68,       8.21                                 (2.4)                                                                             piperidine,                                                                           water        61.50,                                                                            5.58,       8.03                                     piperidine,                                                                   benzoic acid                                           29A13                                                                             S +   Br  91-93                                                                              41.2                                                                              4-Methyl-                                                                             Diethyl                                                                             C.sub.22 H.sub.25 BrO.sub.4 S                                                        56.78,                                                                            5.41,   17.17,                                                                            6.89                                 (1.98)                                                                            piperidine,                                                                           ether-       56.76,                                                                            5.41,   17.12,                                                                            6.66                                     piperidine,                                                                           hexane                                                                benzoic acid                                           29A14                                                                             O OCH.sub.3                                                                         +   112-113                                                                            20  4-Methyl-                                                                             Ethyl C.sub.23 H.sub.28 O.sub.6                                                            68.98,                                                                            7.05                                             (0.77)                                                                            piperidine,                                                                           acetate-     68.99,                                                                            7.04                                                 piperidine,                                                                           hexane                                                                benzoic acid                                           __________________________________________________________________________

EXAMPLE 29Bα-[[3-(1,1-dimethylethyl)-4-hydroxy-5-methylphenyl]-methyene]-β-oxo-2-thiophenepentanoicacid, ethyl ester.

A mixture of ethyl-3-oxo-5-(2-thienyl)-pentanoate² (4.0 g, 0.176 mole),3-tert-butyl-5-methyl-4-hydroxybenzaldehyde³ (2.0 g, 0 01 mole),piperidine (0.2 g), 4-methylpiperidine (0.2 g), benzoic acid (0.2 g) intoluene (300 ml) is refluxed under nitrogen for 23 hours. Water iscollected with a Dean-Stark trap. The mixture is cooled, diluted withether (100 ml) and washed successively with 5% hydrochloric acid (2×500ml), water (500 ml), sodium bicarbonate solution 92×500 ml), and water(2×500 ml). The extract is dried over sodium sulfate and the solvent isremoved under reduced pressure. The crude oil (7 g) is chromatographedon silica gel column. Elution with methylene chloride gives afterrecrystallization from ethyl acetate-hexane 1.93 g (46.4%) ofα-[[3-(1,1-dimethyl-ethyl)-4-hydroxy-5-methylphenyl)-methylene]-oxo-2-thiophenepentanoic acid,ethyl ester, mp 97°-99° C. C, H, S analysis: Calculated for C₂₈ H₂₈ O₄ S(68.97, 7.05, 8.0); Found (68.72, 7.06, 8.30).

EXAMPLES 30 AND 31

The procedure described in Example 29 is repeated to prepare thefollowing α-((4-hydroxy-3,5-disubstituted phenyl)methylidine-β-oxo-pentanoic acid, ethyl esters, starting fromappropriately substituted 4-hydroxy-benzaldehyde and ethyl5-(aryl)-3-oxo-pentanoate in presence of piperidine or methyl piperidineas base in each case:

EXAMPLE 30α-[(4-Hydroxy-3,5-di-tert-butylphenyl)methylidine]-β-oxo-5-(2-furan)pentanoicacid, ethyl ester

Mp 80°-2° C.

EXAMPLE 31α-[(4-Hydroxy-3,5-dimethoxyphenyl)methylidine]-β-oxo-5-phenylpentanoicacid, ethyl ester

Mp 109.5°-111.5° C. starting from ethyl 5-phenyl-3-oxo-pentanoate⁴ andsyringic aldehyde.

EXAMPLE 32α-[(4-Hydroxy-3,5-dimethoxyphenyl)methylidine]-β-oxo-5-(2-furan)pentanoicacid

A mixture of ethylα-[(4-hydroxy-3,5-dimethoxyphenyl)methylene]-β-oxo-5-(2-furan)pentanoate(20 g, 0.053 mol) and aqueous methanolic potassium hydroxide solution[prepared from potassium hydroxide (10.6 g), water (75 ml) and methanol(125 ml)] is heated to reflux on a steam bath for 3.0 hours. Methanol isremoved under reduced pressure and the residue is diluted with water(450 ml), extracted with ether and then acidified with 4 N HCl. Theacidic material is extracted with ethyl acetate as usual to give 6.35 g(34%) of the acid, mp 135° C. (dec). It is recrystallized from ethylacetate to give an analytical sample, mp 135° C. (dec).

EXAMPLE 32A1-[2-[(3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)-methylene]-5-(2-furanyl)-1,3-dioxopentyl)-piperidine

According to the procedure of Example 29, Method 2,1-[2-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-methylene]-5-(2-furanyl)-1,3-dioxopentyl]-piperidineis prepared from ethyl-3-oxo-5-(2-furyl)-pentanoate (21.0 g, 0.1 mole),3,5-di-tert-butyl-4-hydroxybenzaldehyde (12.07 g, 0.05 mole), piperidine(4 ml), acetic acid (12 ml), and toluene (500 ml).

Recrystallization from methanol gives 6.53 g (25%) of1-2-(3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylene]-5-(2furanyl)-1,3-dioxopentyl]-piperidine, mp 155°-157° C. C,H, N analysis: Calculated for C₂₉ H₃₉ NO₄ (74.80, 8.44, 3.07); Found(74.85, 8.41, 2.89).

EXAMPLE 33(E)1-[(3,5-Dimethoxy-4-hydroxy)phenyl]-5-(2-furanyl)1-penten-3-one

4-(2-Furanyl)-2-butanone (7.8 g, 0.056 mol) is added to a solution ofpyrrolidine (7.1 g, 0.1 mol) in acetic acid (6.0 g, 0.1 mol) and themixture is stirred at 23° C. for 28 min. A solution of syringic aldehyde(9.8 g, 0.054 mol) in THF (70 ml) is then added dropwise and the mixtureis stirred for 72 hours. The reaction mixture is added to 5% HCl and thecontents are stirred for 3.0 hours. The product is extracted with ethylacetate, dried and concentrated to give 4.95 g of residue. This ischromatographed over silica gel and eluted with CHCl₃ -CH₃ OH (95:5)mixture to give a solid which is recrystallized from isopropyl ether.Yield 1.4 g (9%), mp 107°-9° C.

EXAMPLE 34(E)4-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)-1-phenoxy-3-buten-2-one

A solution of 3,5-di-t-butyl-4-hydroxy benzaldehyde (3.75 g, 0.016 mol)and 1-phenoxy-3-(triphenylphosphoranylidene)-2-propanone (Wittigreagent)⁵ (9.85 g, 0.024 mol) in xylene (200 ml) is heated under refluxfor six hours in a nitrogen atmosphere. An additional amount (6.6 g;0.016 mol) of Wittig reagent is added and refluxing continued for sixmore hours. The dark brown reaction mixture is filtered through silicagel 60 (60 g) and then chromatographed over silica gel eluting with1:2-EtOAc-cyclohexane. The dark-brown fractions containing product aretreated with charcoal and then rechromatographed on a flashchromatography column (75 g silica gel 60, 230-400 mesh) eluting with10% EtOAc-cyclohexane. The isolated pure product is recrystallized frompentane as golden tan crystals (1.31 g, 22%), mp 100°-101.5° C.

EXAMPLES 35-39

The procedure described in Example 34 is repeated to prepare thefollowing 4-[(substituted-4-hydroxyphenyl)-1-phenoxy (or substitutedphenoxy)]-3-buten-2-ones, starting from appropriatelysubstituted-4-hydroxybenzaldehyde and appropriate Wittig reagents ineach case.

    __________________________________________________________________________    Example                                                                            T and R.sub.1                                                                        Ar          Solvent                                                                            mp                                               __________________________________________________________________________    35   3,5-(OCH.sub.3).sub.2                                                                phenyl      toluene                                                                            149-150° C.                               36   3,5-(iso-Pr).sub.2                                                                   phenyl      toluene                                                                              117-119.5° C.                           37   3,5-(t-Bu).sub.2                                                                     4-(CH.sub.2 COOCH.sub.3)phenyl                                                            xylene                                                                             101.5-103° C.                             38   3,5-(OCH.sub.3).sub.2                                                                4-(CH.sub.2 COOCH.sub.3)phenyl                                                            toluene                                                                            116.5-119.5° C.                           39   3-OCH.sub.3                                                                          4-(CH.sub.2 COOCH.sub.3)phenyl                                                            toluene                                                                            97-98° C.                                 __________________________________________________________________________

EXAMPLE 39A(E)-4-[[4-(4-hydroxy-3,5-dimethylphenyl)-2-oxo-3-butenyl]-oxy]-benzeneacetic acid, Method C

Methyl(E)-4-[[4-(4-hydroxy-3,5-dimethylphenyl)-2-oxo-3-butenyl]oxy]-benzeneacetate (1.73 g) (0.00488 mole) is dissolved in 150 ml 0.1 N NaOH andwarmed on the steam bath. As soon as a temperature of 70° is reached thereaction mixture is removed from the bath and allowed to cool to 50°, atwhich point 1 N HCl (17 ml) is added slowly. The precipitated solid isfiltered off, washed with H₂ O, and recrystallized from HOAc-H₂ O toyield yellow crystals, 1.22 g (73%), mp 151°-153.5° C. Anal. for C₂₀ H₂₀O₅ : Calc. C 70.58, H 5.92; Fd. C 70.48, H 5.72.

                                      TABLE 5                                     __________________________________________________________________________     ##STR32##                                                                                                          Wittig                                                                        Reagant                                                                            Yield                              Exam-                         Recrystn.                                                                             Aldehyde                                                                           in  %                              ple T     R.sup.2                                                                             Q.sub.1 M.P.  Solvent Ratio                                                                              Grams                                                                             Yield                                                                             Analysis                   __________________________________________________________________________    39A1                                                                              (CH.sub.3).sub.3 C                                                                  (CH.sub.3).sub.3 C                                                                  H       100-101.5°                                                                   n Pentane                                                                             2.5  1.31                                                                              22  Calc                                                                             C, 78.65; H, 8.25                                                          Fd C, 78.56; H, 8.44       39A2                                                                              CH.sub.3 O                                                                          Br    H       144-145.5°                                                                   EtOAcC.sub.6 H.sub.12                                                                 1    3.9 72  Calc                                                                             C, 56.22; H, 4.16;                                                            Br, 22.00                                                                  Fd C, 56.48; H, 4.26;                                                            Br, 21.83               39A3                                                                              Br    Br    H       143-145°                                                                     EtOAcC.sub.6 H.sub.12                                                                 2    5.3 64  Calc                                                                             C, 46.63; H, 2.94;                                                            Br, 38.78                                                                  Fd C, 46.51; H, 2.97;                                                            Br, 38.56               39A4                                                                              CH.sub.3 O                                                                          CH.sub.3 O                                                                          3-CH.sub.2 COOCH.sub.3                                                                99-100°                                                                      EtOAcC.sub.6 H.sub.12                                                                 1    0.8 10  Calc                                                                             C, 66528; H, 5.75                                                          Fd C, 65.38; H, 5.64       39A5                                                                              Cl    Cl    H       140-141.5°                                                                   EtOAc   1    6.59                                                                              51  Calc                                                                             C, 59.47; H, 3.74;                                                            Cl, 21.94                                                                  Fd C, 59.43; H, 3.58;                                                            Cl, 21.86               39A6                                                                              Br    Br    4-CH.sub.2 COOCH.sub.3                                                                116-120°                                                                     EtOAcC.sub.6 H.sub.12                                                                 1.1  5.3 55  Calc                                                                             C, 47.14; H, 3.33;                                                            Br, 33.01                                                                  Fd C, 47.17; H, 3.09;                                                            Br, 32.75               39A7                                                                              CH.sub.3                                                                            CH.sub.3                                                                            H       92.5-94.5°                                                                   EtOAc-n-                                                                              0.96 7.5 33  Calc                                                                             C, 76.57; H, 6.43                                     hexane               Fd C, 76.54; H, 6.53       39A8                                                                              CH.sub.3                                                                            CH.sub.3                                                                            4-CH.sub.2 COOCH.sub.3                                                                133-136°                                                                     EtOAcEt.sub.2 O                                                                       1    2.4 35  Calc                                                                             C, 71.17; H, 6.26                                                          Fd C, 70.97; H, 6.27       39A9                                                                              (CH.sub.3).sub.3 C                                                                  (CH.sub.3).sub.3 C                                                                  3-CH.sub.2 COOCH.sub.3                                                                90.5-92.5°                                                                   n-Pentane                                                                             1    1.08                                                                              11  Calc                                                                             C, 73.95; H, 7.81                                                          Fd C, 74.32; H,            __________________________________________________________________________                                                          7.79                

EXAMPLE 40 (Intermediate Wittig Reagent)1-Triphenylphosphoranylidene-3-(4'-methoxyacetylphenoxy)-2-propanone

(A compound of the formula V wherein n is 1, Y is O and Ar is phenylhaving a para substituent of the formula CH₃ O₂ CCH₂)

A solution of methyl 4-hydroxyphenyl acetate (40 g, 0.24 mol) in dry THF(300 ml) is added to a cold (0`-5° C.) suspension of NaH (10 g, 60% oildispersion, 0.25 mol) in THF (150 ml) over 45 min. After the addition iscomplete, the mixture is stirred at 23° C. for 1.5 hours.1-Chloro-3-triphenyl phosphoranylidene)-2-propanone (77.6 g; 0.22 mol)is added in one lot to the anion and then refluxed for 5.0 hours. Thereaction mixture is cooled, decomposed with acetic acid (10 ml) and thenevaporated to dryness. The residue is suspended in 0.33 N HCl (300 ml)and then extracted with CH₂ Cl₂. The organic layer is washed withsaturated NaHCO₃ solution, dried (MgSO₄) and evaporated to dryness. Thecrude product of formula V having n, Y and Ar as defined above isrecrystallized from EtOAc as white crystals. Yield 73.5 g (63.5%), mp143.5°-145.5° C.

EXAMPLE 40A

The procedure described in Example 40 is repeated to prepare1-triphenylphosphoranylidene-3-31/2-methoxyacetylphenoxy) -2-propanone,starting from methyl-3-hydroxyphenylacetate and appropriate Wittigreagent, mp 118°-119° C. (EtOAc-c-C₆ H₁₂) (chromatography required).Yield 19.9 g (41%).

EXAMPLE 41(E)-1-[(3,5-Dimethoxy-4-hydroxy)phenyl]-4-phenoxy-1-buten-3-one oxime

A solution of(E)-4-(4-hydroxy-3,5-dimethoxyphenyl)-1-phenoxy-3-buten-2-one (0.95 g,0.003 mol) and hydroxylamine hydrochloride (0.42 g, 0.006 mol) in1:1-pyridine-ethanol (10 ml) is heated under reflux for 2.0 hours. Thereaction mixture is evaporated to near dryness and then suspended inwater (50 ml) and extracted with ether. The ether extracts areevaporated to dryness and the residue is chromatographed over silica gel60 (30 g) eluting with EtOAc-toluene (1:2). The purified product isrecrystallized from Et₂ O. Yield 0.29 g (29.4%), mp 144°-147° C.

The usefulness of the compounds of the present invention as inhibitorsof lipoxygenase enzyme or other related biochemical actions isdemonstrated by their effectiveness in various standard test procedures.A description of each procedure follows.

EXAMPLE 41A.4-[[4-[3,5-bid-(1,1-dimethylethyl)-4-hydroxyphenyl)-2-hydroxyimino-3-butenyl]oxy]-benzoicacid, methyl ester Method A

A solution of4-[[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-2-oxo-3-butenyl]oxy]benzoicacid, methyl ester (3.07 g, .007 mole), hydroxylamine HCl (1.46 g, 0.21mole) and NaOAc (1.72 g, .021 mole) in 100 ml MeOH is allowed to standat room temperature for 48 hours. The reaction mixture is evaporated todryness and the residue is taken up in H₂ O and extracted with CHCl₃.The CHCl₃ extract is dried over Na₂ SO₄ and evaporated to dryness. Theresidue is flash-chromatographed on silica gel, eluting with CH₂ Cl₃ andEtoAc-CH₂ Cl₃. The fractions containing the product are combined,yielding 1.41 g (44%) white amorphous solid, mp 53°-65° C. Anal, for C₂₇H₃₅ NO₅. Calculated C 71.50, H 7.78, N 3.09; Found C 71.42, H 7.81, N2.77.

    TABLE 6      ##STR33##               Recrystn. Amount   No. T R.sub.2 X Y Z Ar M.P. Solvent Grams %     Yield Analysis       41A1 CH.sub.3 O H H O CH.sub.2 O 4-C.sub.6 H.sub.4 CH.sub.2 COOH     147-150° HOAcH.sub.2 O 0.76 61 Calc C, 66.66; H, 5.30     Fd C, 66.38; H, 5.14  41A2 Br Br H O CH.sub.2 O 4-C.sub.6 H.sub.4     CH.sub.2 COOH 142-166° HOAcH.sub.2 O 0.23 24 Calc C, 45.99; H,     3.00; Br, 33.99            Fd C, 45.76; H, 2.79; Br, 33.72  41A3     CH.sub.3 CH.sub.3 H O CH.sub.2 O 4-C.sub.6 H.sub.4 CH.sub. 2 COOH     151-153.5° HOAcH.sub.2 O 1.22 73 Calc C, 70.58; H, 5.92      Fd C, 70.48; H, 5.72  41A4 Cl Cl H NOH CH.sub.2 O C.sub.6 H.sub.5     177-181° Et.sub.2 OC.sub.6 H.sub.12 1.7 34 Calc C, 56.82; H,     3.87; N, 4.14; Cl, 20.97            Fd C, 56.62; H, 3.82; N, 4.13; Cl,     21.20  41A5 (CH.sub.3).sub.3 C (CH.sub.3 C).sub.3 C H O CH.sub.2 O     4-C.sub.6 H.sub.4 CH.sub.2 COOH 146-147.5° Et.sub.2 OC.sub.6     H.sub.12 1.37 81 Calc C, 73.56; H, 7.60            Fd C, 73.57; H, 7.65     41A6 CH.sub.3 O H H NOH CH.sub.2 S C.sub.6 H.sub.5 133.5-135°     Et.sub.2 OC.sub.6 H.sub.12 0.41 28 Calc C, 64.74; H, 5.43; N, 4.44; S,     10.17     (single isomer)       Fd C, 64.47; H, 5.43; N, 4.43; S, 9.87     41A7 CH.sub.3 O H H NOH CH.sub.2 S C.sub.6 H.sub.5 104.5-110°     CHCl.sub.3C.sub.6 H.sub.12 1.43 22 Calc C, 64.74; H, 5.43; N, 4.44; S,     10.17            Fd C, 64.72; H, 5.17; N, 4.31; S, 9.95  41A8 CH.sub.3 O     CH.sub.3 O H O CH.sub.2 O 3-C.sub.6 H.sub.4 CH.sub.2      COOH 126-128° HOAcH.sub.2 O 0.96 52 Calc C, 64.51; H, 5.41          Fd C, 64.57; H, 5.46  41A9 Br Br H NOH CH.sub.2 O 4-C.sub.6 H.sub.4     CH.sub.2 COOCH.sub.3 144-153° n-hexane 0.56 37 Calc C, 45.72; H,     3.43; N, 2.81; Br, 32.02            Fd C, 45.66; H, 3.40; N, 2.68; Br,     31.92   41A10 CH.sub.3 CH.sub.3 H NOH CH.sub.2 O C.sub.6 H.sub.5     177-179° EtOAc 0.95 32 Calc C, 72.71; H, 6.44; N, 4.71     (single isomer)     n-hexane  Fd C, 72.66; H, 6.34; N, 4.53   41A11 Br     Br H NOH CH.sub.2 O C.sub.6 H.sub.5 179.5-180.5° Et.sub.2     OC.sub.6 H.sub.12 0.85 40 Calc C, 45.00; H, 3.07; N, 3.28; Br, 37.42            Fd C, 44.84; H, 3.05; N, 3.61; Br, 37.40

EXAMPLE 424-(5-Bromo-4-hydroxy-5-methoxyphenyl)-1-phenoxy-3-buten-2-one, oxime(Isomer A) and4-(5-Bromo-4-hydroxy-5-methoxyphenyl)-1-phenoxy-3-buten-2-one, oxime(mixture of Isomer A and Isomer B)

A solution of(E)-4-(5-Bromo-4-hydroxy-5-methoxyphenyl)-1-phenoxy-3-buten-2-one (2.54g, 0.007 mole), hydroxylamine hydrochloride (1.46 g, 0.021 mole), NaOAc(1.72 g, 0.021 mole) in 150 ml MeOH is allowed to stand for 48 hours.The reaction mixture is evaporated to dryness, taken up in CHCl₋₋ andwashed with H₋₋ O and saturated NaCl. The CHCl₋₋ phase is dried overNa₋₋ SO₋₋, evaporated to dryness, and flash-chromatographed on silicagel, eluting with CH₋₋ Cl₋₋ and EToAc-CH₋₋ Cl₋₋. The fractions yieldinga single oxime isomer are collected and kept separate from thosefractions containing a mixture of the oxime isomers.

The single isomer (Isomer A) fractions are washed with Et₋₋O-cyclohexane to give white crystals, 0.85 g (32%), mp 142°-145° C.

Analysis for C₁₇ H₁₆ NO₄ Br: Calculated, C 53,99 H 4.26, N 3.70, Br21.13. Found, C 53.94, H 4.11, N 3.57, Br 20.86.

The chromatography fractions containing a mixture of oxime isomers(Isomer A and Isomer B) yielded, without further purification, off-whitecrystals, 0.46 g (17%), mp 130°-140° C.

Analy calc for C₁₇ H₁₆ NO₄ Br, C 53.99, H 4.26, N 3.70, Br 21.21; Found,C 54.10, H 4.10, N 3.52, Br, 21.07

5-Lipoxygenase Assay Using Isolated Human Leukocytes (5LOA₂)

The formation of 5-HETE in human leukocytes is considered a measure of5-lipoxygenase activity. The protocol is described in the following.

Fresh heparinized or EDTA treated human blood is mixed with 6%dextran-3% dextrose in isotonic saline in the ratio 0.25 ml dextransolution per 1.0 ml blood. After mixing the blood is allowed to sit atroom temperature for about 90 minutes while the RBC's settle. Duringthis period, the plasma is removed with a plastic pipette to nalgenstubes.

The plasma is centrifuged at 800 rpm (125 kg) on the Beckman Td-brefrigerated centrifuge to remove the platelets (which remain in thesupernatant). The pellet, consisting of leukocytes and erythrocytes, istreated with 10 ml 0.87% ammonium chloride at room temperature for fourminutes, lysing the red cells. At the end of four minutes the cells arediluted with a 2x volume of phosphate buffered saline, pH 7.4, andcentrifuged for ten minutes. The cells are washed three times with thephosphate buffered saline. Any of the pelleted cell matter which is noteasily resuspended is discarded during the washings--the materialcontains platelets (12-lipoxygenase activity).

After washing, the cells are resuspended in phosphate buffered salinecontaining 1.0 mM calcium and 0.5 mM magnesium. After counting, thecells are diluted to 1.5-2.0×10⁻⁷ leukocytes per milliliter.

To each poly propylene reaction tube is added 0.48 ml leukocytes inCa-Mg phosphate buffered saline, pH 7.4; 1-5 μl test compound dissolvedin DMSO and buffer; or DMSO for control tubes.

The tubes preincubate at 37° C. for five minutes.

The reaction is started by adding 20 μl of the following, 0.5 μl 20 mMarachidonic acid--final concentration=20 μm; 1 μl, 5 mM calciumionophore A23187--final concentration=10 μm; and 18.5 μl buffer.

The reaction proceeds for five minutes, then is stopped by adding 0.5ml, 0.5 mM ice cold Tris buffer, pH 8.0. The tubes are chilled on icefor ten minutes and then extracted three times with a total of 3.5 mlethyl acetate (3.0 ml removed).

The tubes can be stored at this point. For extended storage, the tubesshould be filled with nitrogen.

The ethyl acetate is evaporated with a Sorvall Speed-Vac. The residue isdissolved in ethanol. The tubes can also be stored at this point at -20°C. under nitrogen.

A portion of the ethanol solution is injected into the HPLC system for5-HETE quantitation.

The HPLC system consists of Hewlett-Packard 1040A UV spectrophotometrysystem with an HP85 computer. Injections are made automatically with aWaters WISP 710B. The pump is a Spectra Physics SP8700. Peaks aremeasured with a Hewlett Packard 3390A integrator. An RP C-18 column isused. The solvent system is isocratic; the solvent is 70% methanol and30% 0.01M sodium acetate, pH 5.7, pumped at 1.0 ml/min. The flow ismonitored at 235 nm for 5-HETE quantitation. Using a 15 cm AlltechNucleosil C-18 5 μM column provides for a sample turnaround time ofabout 16 minutes.

IC₅₀ is calculated as the amount of test agent that causes 50%inhibition of the formation of 5-HETE relative to the control.

Cyclooxygenase Enzyme Assay (BSV)

Additionally, inhibition of cyclooxygenase is considered a measure ofrelevance to the pathophysiology for the above noted diseases. Forexample, see "Inhibition of Immunoglobulin E-Mediate, Antigen-InducedMonkey Asthma and Skin Reactions by 5,8,11,14-Eicosatetraynoic Acid," byRoy Patterson, M.D. and Kathleen E. Harris, B.S. in J. Allergy Clin.Immunol., vol. 67, no. 2, pp. 146-152.

The assay consists of incubating 2 mg bovine seminal vesicle powder with2 mM epinephrine, 2.5 mM reduced glutathione, 100 μM arachidonic acid,and the test agent for 20 minutes. The reaction mixture is acidified andextracted with ethyl acetate (3×1.0 ml) and the pooled extract isevaporated to dryness using a Speed Vac Concentrator or under a streamof nitrogen. The residue is dissolved in ethanol. An aliquot is appliedon 20×20 cm silica gel plate and developed using water:ethylacetate:hexane:acetic acid (60:54:25:12.5, upper phase) to separate PGE₂from arachidonic acid. ¹⁴ C-PGE₂ formed is identified byco-chromatography with authentic ³ H-PGE₂ and the amount ofradioactivity is quantitated using an automatic TLC linear scanner(Berthold, Pittsburgh, Pennsylvania) linked to an Apple II-e computerand an IC₅₀ is calculated as the amount of test agent causing 50%inhibition of Cyclooxygenase Enzyme relative to the control.

The above defined value for each of tested compounds of the presentinvention having the noted example numbers are as found in the followingTable 7.

                  TABLE 7                                                         ______________________________________                                                       5-LOA     BSV                                                  Example No.    IC.sub.50 (μM)                                                                       IC.sub.50 (μM)                                    ______________________________________                                         1             11.0                                                            2              1.7                                                            3             30% (20)*                                                       4             17% (20)*                                                       5              8.8                                                            6             19% (20)*                                                       7             18.0                                                            8              2.0                                                            9             15.0      31.0                                                 10             18.0      92.0                                                 11             22.0      110.0                                                12             22% (20)* 135.0                                                13             19.0      84.0                                                 14             11.0      31.0                                                 15               0.079   169                                                  16             20.0      130.0                                                16A            12.0                                                           17              1.7      23.0                                                 18              5.9                                                           19              1.0      125.0                                                20              8.7                                                           21               0.420   33.0                                                 22             35.0                                                           23 (Isomer A)    0.165   98.0                                                 23 (Isomer B)   0.26     90.0                                                 24              2.5      57.0                                                 24A                                                                           25              0.71     170.0                                                26              3.0                                                           27                                                                            28                                                                            ______________________________________                                         *% inhibition at 20 μM.                                               

Accordingly, the present invention also includes a pharmaceuticalcomposition for treating one of the above diseases or conditionscomprising an antidisease or anticondition effective amount of acompound of the formula I as defined above together with apharmaceutically acceptable carrier.

The present invention further includes a method for treating one of theabove named diseases or conditions in mammals, including man, sufferingtherefrom comprising administering to such mammals either orally orparenterally, preferably oral, a corresponding pharmaceuticalcomposition containing a compound of formula I as defined above inappropriate unit dosage form.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets, and suppositories. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders or tablet disintegrating agents; it can also be encapsulatingmaterial. In powders, the carrier is a finely divided solid which is inadmixture with the finely divided active compound. In the tablet theactive compound is mixed with carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired. The powders and tablets preferably contain from 5 or 10 toabout 70 percent of the active ingredient. Suitable solid carriers aremagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term "preparation" is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component (with or without other carriers)is surrounded by carrier, which is thus in association with it.Similarly, cachets are included. Tablets, powders, cachets, and capsulescan be used as solid dosage forms suitable for oral administration.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides or cocoa butter is first melted, and the activeingredient is dispersed homogeneously therein as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection. Liquid preparations can also be formulated insolution in aqueous polyethylene glycol solution. Aqueous solutionssuitable for oral use can be prepared by dissolving the active componentin water and adding suitable colorants, flavors, stabilizing andthickening agents as desired. Aqueous suspensions suitable for oral usecan be made by dispersing the finely divided active component in waterwith viscous material, i.e., natural or synthetic gums, resins,methylcellulose, sodium carboxymethylcellulose, and other well-knownsuspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions, and emulsions. These particular solid form preparations aremost conveniently provided in unit dose form and as such are used toprovide a single liquid dosage unit. Alternately, sufficient solid maybe provided so that after conversion to liquid form, multiple individualliquid doses may be obtained by measuring predetermined volumes of theliquid form preparation as with a syringe, teaspoon, or other volumetriccontainer. When multiple liquid doses are so prepared, it is preferredto maintain the unused portion of said liquid doses at low temperature(i.e., under refrigeration) in order to retard possible decomposition.The solid form preparations intended to be converted to liquid form maycontain, in addition to the active material, flavorants, colorants,stabilizers, buffers, artificial and natural sweeteners, dispersants,thickeners, solubilizing agents, and the like. The liquid utilized forpreparing the liquid form preparation may be water, isotonic water,ethanol, glycerine, propylene glycol, and the like as well as mixturesthereof. Naturally, the liquid utilized will be chosen with regard tothe route of administration, for example, liquid preparations containinglarge amounts of ethanol are not suitable for parenteral use.

Preferably, the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, for example, packeted tablets, capsules, and powders invials or ampoules. The unit dosage form can also be a capsule, cachet,or tablet itself or it can be the appropriate number of any of these inpackaged form.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from 1 mg to 500 mg preferably to 1 to 50 mgaccording to the particular application and the potency of the activeingredient. The compositions can, if desired, also contain othercompatible therapeutic agents.

In therapeutic use as described above, the dosages may be varieddepending upon the requirements of the patient, the severity of thecondition being treated, and the compound being employed. Determinationof the proper dosage for a particular situation is within the skill ofthe art. Generally, treatment is initiated with the smaller dosageswhich are less than the optimum dose of the compound. Thereafter thedosage is increased by small increments until the optimum effect underthe circumstances is reached. For convenience, the total daily dosagemay be divided and administered in portions during the day if desired.

As used herein cardiovascular diseases or conditions particularlyinclude 1) reductions of the extent of infarct damage in a myocardialinfarction, 2) prevention of recurrent myocardial infarction, 3) stroke,4) anaphylactic shock, and 5) vasospastic disease.

An additional advantageous benefit of the cytoprotective property of thecompounds of formula I are for use, for example, to protect againstdamage from various GI tract conditions.

Generally accepted assays can be used to measure cytoprotectiveactivity.

The magnitude of a prophylactic or therapeutic dose of a compound offormula I will, of course, vary with the nature of the severity of thecondition to be treated and with the particular compound of formula Iand its route of administration. In general, the daily dose range forantiasthmatic, antiallergic or antiinflammatory use and, generally usesother than cytoprotection, lies within the range of from about 10 μg toabout 20 mg per kg body weight of a mammal, preferably from about 50 μgto about 20 mg per kg of body weight of a mammal, and most preferablyfrom about 100 μg to about 10 mg per kg of body weight of a mammal.

The exact amount of a compound of the formula I to be used as acytoprotective agent will depend on, inter alia, whether it is beingadministered to heal damaged cells or to avoid future damage, on thenature of the damaged cells (e.g., gastrointestinal ulcerations vs.nephrotic necrosis), and on the nature of the causative agent. Anexample of the use of a compound of the formula I in avoiding futuredamage would be co-administration of a compound of the formula I with anonsteroidal antiinflammatory drug (for example, indomethacin) thatmight otherwise cause such damage. For such use, the compound of formulaI is administered from 30 minutes prior up to 30 minutes afteradministration of the NSAID. Preferably, it is administered prior to orsimultaneously with the NSAID (e.g. as a combination dosage form).

The effective daily dosage level for compounds of formula I inducingcytoprotection in mammals, especially humans, will generally range fromabout 0.002 mg/kg to about 100 mg/kg, preferably from about 0.02 mg/kgto about 30 mg/kg. The dosage may be administered in single or dividedindividual doses.

Thus, in addition to the compounds of formula I, the pharmaceuticalcompositions can also contain other active ingredients, such ascyclooxygenase inhibitors, nonsteroidal antiinflammatory drugs (NSAIDs),peripheral analgesic agents such as zomepirac, diflunisal and the like.The weight ratio of the compound of the formula I to the second activeingredient may be varied and will depend upon the effective dose of eachingredient. Generally, an effective dose of each will be used. Thus, forexample, when a compound of the formula I is combined with an NSAID, theweight ratio of the compound of the formula I to the NSAID willgenerally range from about 1000:1 to about 1:1000, preferably about200:1 to about 1:200. Combinations of a compound of the formula I andother active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

Combinations of a compound of the formula I and other active ingredientswill generally be in the aforementioned ratios.

NSAIDs can be characterized into five groups:

(1) the propionic acid derivatives;

(2) the acetic acid derivatives;

(3) the fenamic acid derivatives;

(4) the biphenylcarboxylic acid derivatives; and

(5) the oxicams

or a pharmaceutically acceptable salt thereof.

The propionic acid derivatives which may be used comprise: ibuprofen,ibuprufen aluminum, indoprofen, ketoprofen, naproxen, benoxaprofen,flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen,carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen,alminoprofen, tiaprofenic acid, fluprofen and bucloxic acid.Structurally related propionic acid derivatives having similar analgesicand antiinflammatory properties are also intended to be included in thisgroup.

Thus, "propionic acid derivatives" as defined herein are nonnarcoticanalgesics/nonsteroidal antiinflammatory drugs having a free--CH(CH₃)COOH or --CH₂ CH₂ COOH group (which optionally can be in theform of a pharmaceutically acceptable salt group, e.g., --CH(CH₃)COO⁻Na⁺ or --CH₂ CH₂ COO⁻ Na⁺), typically attached directly or via acarbonyl function to a ring system, preferably to an aromatic ringsystem.

The acetic acid derivatives which may be used comprise: indomethacin,which is a preferred NSAID, sulindac, tolmetin, zomepirac, diclofenac,fenclofenac, alclofenac, ibufenac, isoxepac, furofenac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac, oxpinac, and fenclozicacid. Structurally related acetic acid derivatives having similaranalgesic and antiinflammatory properties are also intended to beencompassed by this group.

Thus, "acetic acid derivatives" as defined herein are nonnarcoticanalgesics/nonsteroidal antiinflammatory drugs having a free --CH₂ COOHgroup (which optionally can be in the form of a pharmaceuticallyacceptable salt group, e.g. --CH₂ COO⁻ NA⁺), typically attached directlyto a ring system, preferably to an aromatic or heteroaromatic ringsystem.

The fenamic acid derivatives which may be used comprise: mefenamic acid,meclofenamic acid, flufenamic acid, niflumic acid and tolfenamic acid.Structurally related fenamic acid derivatives having similar analgesicand antiinflammatory properties are also intended to be encompassed bythis group.

Thus, "fenamic acid derivatives" as defined herein are nonnarcoticanalgesics/nonsteroidal antiinflammatory drugs which contain the basicstructure: ##STR34## which can bear a variety of substituents and inwhich the free -COOH group can be in the form of a pharmaceuticallyacceptable salt group, e.g., --COO⁻ Na⁺.

The biphenylcarboxylic acid derivatives which can be used comprise:diflunisal and flufenisal. Structurally related biphenylcarboxylic acidderivatives having similar analgesic and antiinflammatory properties arealso intended to be encompassed by this group.

Thus, "biphenylcarboxylic acid derivatives" as defined herein arenonnarcotic analgesics/ nonsteroidal antiinflammatory drugs whichcontain the basic structure: ##STR35## which can bear a variety ofsubstituents and in which the free --COOH group can be in the form of apharmaceutically acceptable salt group, e.g., --COO⁻ Na⁺.

The oxicams which can be used in the present invention comprise:piroxicam, sudoxicam, isoxicam and 4-hydroxyl-1,2-benzothiazine1,1-dioxide 4-(N-phenyl)-carboxamide. Structurally related oxicamshaving similar analgesic and antiinflammatory properties are alsointended to be encompassed by this group.

Thus, "oxicams" as defined herein are nonnarcoticanalgesics/non-steroidal antiinflammatory drugs which have the generalformula: ##STR36## wherein R is an aryl or heteroaryl ring system.

The following NSAIDs may also be used: acemetacin, alminoprofen, amfenacsodium, aminoprofen, anitrazafen, antrafenine, auranofin, bendazaclysinate, benzydamine, beprozin, broperamole, bufezolac, carprofen,cinmetacin, ciproquazone, clidanac, cloximate, dazidamine, deboxamet,delmetacin, detomidine, dexindoprofen, diacerein, di-fisalamine,difenpyramide, emorfazone, enfenamic acid, enolicam, epirizole,etersalate, etodolac, etofenamate, fanetizole mesylate, fenclofenac,fenclorac, fendosal, fenflumizole, fentiazac, feprazone, floctafenine,flunixin, flunoxaprofen, fluproquazone, fopirtoline, fosfosal,furcloprofen, furofenac, glucametacin, guaimesal, ibuproxam, isofezolac,isonixim, isoprofen, isoxepac, isoxicam, lefetamine HCl, leflunomide,lofemizole, lonazolac calcium, lotifazole, loxoprofen, lysinclonixinate, meclofenamate sodium, meseclazone, microprofen, nabumetone,nictindole, nimesulide, orpanoxin, oxametacin, oxapadol, oxaprozin,perisoxal citrate, pimeprofen, pimetacin, piproxen, pirazolac,pirfenidone, pirprofen, pranoprofen, proglumetacin maleate, proquazone,pyridoxiprofen, sudoxicam, suprofen, talmetacin, talniflumate,tenoxicam, thiazolinobutazone, thielavin B, tiaprofenic acid, tiaramideHCl, tiflamizole, timegadine, tioxaprofen, tolfenamic acid, tolpadol,tryptamid, ufenamate, and zidometacin.

Finally, NSAIDs which may also be used include the salicylates,specifically aspirin, and the phenylbutazones, and pharmaceuticallyacceptable salts thereof.

Pharmaceutical compositions comprising the formula I compounds may alsocontain as the second active ingredient, antihistaminic agents such asbenadryl, dramamine, histadyl, phenergan and the like. Alternatively,they may include prostaglandin antagonists such as those disclosed inEuropean Patent Application 11,067 or thromboxane antagonists such asthose disclosed in U.S. Pat. No. 4,237,160. They may also containhistidine decarboxylase inhibitors such as α-fluoromethylhistidine,described in U.S. Pat. No. 4,325,961. The compounds of the formula I mayalso be advantageously combined with an H₁ or H₂ -receptor antagonist,such as for instance cimetidine, ranitidine, terfenadine, famotidine,aminothiadiazoles disclosed in EP 81102976.8 or temelastine,acrivastine, loratadine, cetrizine, tazifylline, azelastine and likecompounds, such as those disclosed in U.S. Pat. Nos. 4,283,408;4,362,736; 4,394,508 and European Patent Application No. 40,696. Thepharmaceutical compositions may also contain a K⁺ /H⁺ ATPase inhibitorsuch as omeprazole, disclosed in U.S. Pat. No. 4,255,431, and the like.Each of the references referred to in this paragraph is herebyincorporated herein by reference.

We claim: 1.1-penten-3-one,5-(2-furanyl)-1-(4-hydroxy-3,5-dimethoxyphenyl)-, 1-penten-3-one,1-(3-bromo-4-hydroxy-5-methoxyphenyl)-5-(2-furanyl), 1-penten-3-one,5-(2-furanyl)-1-(4-hydroxy-3,5-dimethoxyphenyl)-, oxime, 1-penten-3-one,1-(4-hydroxy-3-methoxyphenyl)-5-(2-thienyl)-, 1-penten-3-one,1-(4-hydroxy-3,5-dimethoxyphenyl)-5-(2-thienyl)-, 1-penten-3-one,1-(4-hydroxy-3,5-dimethoxyphenyl)-5-(2-thienyl)-, oxime, 1-penten-3-one,1-(4-hydroxy-3-methoxyphenyl)-5-(2-thienyl)-, oxime, 1-penten-3-one,1-(4-hydroxy-3,5-dimethylphenyl)-5-(2-thienyl)-, 1-penten-3-one,5-(2-furanyl-1-(4-hydroxy-3,5-dimethylphenyl-, 1-penten-3-one,1-(4-hydroxy-3,5-dimethylphenyl)-5-(2-thienyl)-, oxime, 1-penten-3-one,5-(2-furanyl)-1-(4-hydroxy-3,5-dimethylphenyl)-, oxime, 1-penten-3-one,1-[3-(1,1-dimethylethyl)-4-hydroxyphenyl]-5-(2-furanyl)-,1-penten-3-one, 1-[3-1,1-dimethylethyl)-4-hydroxyphenyl]-5-(2-furanyl)-,oxime (E)-(+)-, 1-penten-3-one,1-[3-(1,1-dimethylethyl)-4-hydroxy-5-methoxyphenyl]-5-(2-furanyl)-,(E)-, 2-furancarboxylic acid,5-[5-(3-bromo-4-hydroxy-5-methoxyphenyl)-3-oxo-4-pentenyl]-, methylester, (E)-, 2-furancarboxylic acid,5-[5-[3-(1,1-dimethylethyl)-4-hydroxyphenyl]-3-oxo-4-pentenyl]-, methylester, (E)-, 2-furancarboxylic acid, 5-[5-(4-hydroxy-3-methoxyphenyl)-3-oxo-4-pentenyl]-, methyl ester, (E)-, 2-furancarboxylic acid,5-[5-(4-hydroxy-3-methoxyphenyl)-3-hydroxyimino)-4-pentenyl]-, methylester, 2-furancarboxylic acid,5-[3-hydroxyimino)-5-(4-hydroxy-3-methoxyphenyl)-4-pentenyl]-, (E)-,1-penten-3-one, 1-(3-bromo-4-hydroxy-5-methoxyphenyl)-5-(2-furanyl)-,oxime (E,E)-, 1-penten-3-one,1-(3-bromo-4-hydroxy-5-methoxyphenyl)-5-(2-furanyl)-, oxime, (Z,E)-,2-furanpentanoic acid, α-[(4-hydroxy-3,5-dimethoxyphenyl)methylene]-β-oxo-, ethyl ester, 2-furanpentanoic acid,α-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-β-oxo-, ethylester, 2-furanpentanoic acid, α-[(3,5-dibromo-4-hydroxyphenyl)methylene]-β-oxo-, ethyl ester, 2-furanpentanoic acid,α-[(3-bromo-4-hydroxy-5-methoxyphenyl)methylene]-β-oxo-, ethyl ester,2-furanpentanoic acid, α-[(4-hydroxy-3-methoxyphenyl) methylene]-β-oxo,ethyl ester, 2-furanpentanoic acid, α-[(3,5-dichloro-4-hydroxyphenyl)methylene]-β-oxo-, ethyl ester 2-furanpentanoic acid,α-[[3-(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-β-oxo, ethyl ester,2-thiophenepentanoic acid,α-[(4-hydroxy-3,5-dimethylphenyl)methylene]-β-oxo, ethyl ester,2-furanpentanoic acid, α-[(4-hydroxy-3,5-dimethylphenyl)methylene]-β-oxo-, ethyl ester, 2-furanpentanoic acid,α-[[3-(1,1-dimethylethyl)-4-hydroxy-5-methylphenyl]methylene]-oxo-,ethyl ester, 2-thiophenepentanoic acid,α-[[3,5-bis(1,1-dimethylethyl0-4-hydroxyphenyl]methylene]-oxo, ethylester, 2-furanpentanoic acid,α-[[3-bromo-5-(1,1-dimethylethyl)-4-hydroxyphenyl]methylene-β-oxo-,ethyl ester, 2-thiophenepentanoic acid,α-[(4-hydroxy-3,5-dimethoxyphenyl)methylene]-β-oxo-, ethyl ester,2-thiophenepentanoic acid, α-[[3-bromo-5-(1, 1-dimethylethyl)-4-hydroxyphenyl]methylene-β-oxo-, ethyl ester, 2-furanpentanoic acid,α-[[3-(1,1-dimethylethyl)-4-hydroxy-5-methoxyphenyl]methylene]-.beta.-oxo,ethyl ester, 2-thiophenepentanoic acid,α-[[3-(1,1-dimethylethyl)-4-hydroxy-5-methylphenyl]methylene]-β-oxo,ethyl ester, piperidine,1-[2-[[3,5-dis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-5-(2-furanyl)-1,3-dioxopentyl]-.2. A compound of claim 1 which is 1-penten-3-one,5-(2-furanyl)-1-(4-hydroxy-3,5-dimethoxyphenyl)-.
 3. A compound of claim1 which is 1-penten-3-one,1-(3-bromo-4-hydroxy-5-methoxyphenyl)-5-(2-furanyl).
 4. A compound ofclaim 1 which is 1-penten-3-one,5-(2-furanyl)-1-(4-hydroxy-3,5-dimethoxyphenyl)-, oxime.
 5. A compoundof claim 1 which is 1-penten-3-one,1-(4-hydroxy-3-methoxyphenyl)-5-(2-thienyl)-.
 6. A compound of claim 1which is 1-penten-3-one,1-(4-hydroxy-3,5-dimethoxyphenyl)-5-(2-thienyl)-.
 7. A compound of claim1 which is 1-penten-3-one,1-(4-hydroxy-3,5-dimethoxyphenyl)-5-(2-thienyl)-, oxime.
 8. A compoundof claim 1 which is 1-penten-3-one,1-(4-hydroxy-3-methoxyphenyl)-5-(2-thienyl)-, oxime,
 9. A compound ofclaim 1 which is 1-penten-3-one,1-(4-hydroxy-3,5-dimethylphenyl)-5-(2-thienyl)-.
 10. A compound of claim1 which is 1-penten-3-one,5-(2-furanyl)-1-(4-hydroxy-3,5-dimethylphenyl)-.
 11. A compound of claim1 which is 1-penten-3-one,1-(4-hydroxy-3,5-dimethylphenyl)-5-(2-thienyl)-, oxime.
 12. A compoundof claim 1 which is 1-penten-3-one,5-(2-furanyl)-1-(4-hydroxy-3,5-dimethylphenyl)-, oxime.
 13. A compoundof claim 1 which is 1-penten-3-one,1-[3-(1,1-dimethylethyl)-4-hydroxyphenyl]-5-(2-furanyl)-.
 14. A compoundof claim 1 which is 1-penten-3-one,1-[3-1,1-dimethylethyl)-4-hydroxyphenyl]-5-(2-furanyl)-, oxime (E)-(+)-.15. A compound of claim 1 which is 1-penten-3-one,1-[3-(1,1-dimethylethyl)-4-hydroxy-5-methoxyphenyl]-5-(2-furanyl)-,(E)-.
 16. A compound of claim 1 which is 2-furancarboxylic acid,5-[5-(3-bromo-4-hydroxy-5-methoxyphenyl)-3-oxo-4-pentenyl]-, methylester, (E)-.
 17. A compound of claim 1 which is 2-furancarboxylic acid,5-[5-[3-(1,1-dimethylethyl)-4-hydroxyphenyl]-3-oxo-4-pentenyl]-, methylester, (E)-.
 18. A compound of claim 1 which is 2-furancarboxylic acid,5-[5-(4-hydroxy-3-methoxyphenyl) -3-oxo-4-pentenyl]-, methyl ester,(E)-.
 19. A compound of claim 1 which is 2-furancarboxylic acid,5-[5-(4-hydroxy-3-methoxyphenyl)-3-(hydroxyimino)-4-pentenyl]-, methylester.
 20. A compound of claim 1 which is 2-furancarboxylic acid,5-[3-(hydroxyimino)-5-(4-hydroxy-3-methoxyphenyl)-4-pentenyl]-, (E)-.21. A compound of claim 1 which is 1-penten-3-one,1-(3-bromo-4-hydroxy-5-methoxyphenyl)-5-(2-furanyl)-, oxime (E,E)-. 22.A compound of claim 1 which is 1-penten-3-one,1-(3-bromo-4-hydroxy-5-methoxyphenyl)-5-(2-furanyl)-, oxime, (Z,E)-. 23.A compound of claim 1 which is 2-furanpentanoic acid,α-[(4-hydroxy-3,5-dimethoxyphenyl) methylene]-β-oxo-, ethyl ester.
 24. Acompound of claim 1 which is 2-furanpentanoic acid,α-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-β-oxo-, ethylester.
 25. A compound of claim 1 which is 2-furanpentanoic acid,α-[(3,5-dibromo-4-hydroxyphenyl) methylene]-β-oxo-, ethyl ester.
 26. Acompound of claim 1 which is 2-furanpentanoic acid,α-[(3-bromo-4-hydroxy-5-methoxyphenyl)methylene]-β-oxo-, ethyl ester,27. A compound of claim 1 which is 2-furanpentanoic acid,α-[(4-hydroxy-3-methoxyphenyl) methylene]-β-oxo, ethyl ester.
 28. Acompound of claim 1 which is 2-furanpentanoic acid,α-[(3,5-dichloro-4-hydroxyphenyl) methylene]-β-oxo-, ethyl ester.
 29. Acompound of claim 1 which is 2-furanpentanoic acid,α-[[3-(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-β-oxo-, ethylester.
 30. A compound of claim 1 which is 2-thiophenepentanoic acid,α-[(4-hydroxy-3,5-dimethylphenyl)methylene]-β-oxo-, ethyl ester.
 31. Acompound of claim 1 which is 2-furanpentanoic acid,α-[(4-hydroxy-3,5-dimethylphenyl)methylene]-β-oxo-, ethyl ester.
 32. Acompound of claim 1 which is 2-furanpentanoic acid,α-[[3-(1,1-dimethylethyl)-4-hydroxy-5-methylphenyl]methylene]-oxo-,ethyl ester,
 33. A compound of claim 1 which is 2-thiophenepentanoicacid, α-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-oxo-,ethyl ester.
 34. A compound of claim 1 which is 2-furanpentanoic acid,α-[[3-bromo-5-(1,1-dimethylethyl)-4-hydroxyphenyl]methylene-β-oxo-,ethyl ester.
 35. A compound of claim 1 which is 2-thiophenepentanoicacid, α-[(4-hydroxy-3,5-dimethoxyphenyl)methylene]-β-oxo-, ethyl ester.36. A compound of claim 1 which is 2-thiophenepentanoic acid,α-[[3-bromo-5-(1,1-dimethylethyl)-4-hydroxyphenyl]methylene-β-oxo-,ethyl ester.
 37. A compound of claim 1 which is 2-furanpentanoic acid,α-[[3-(1,1-dimethylethyl)-4-hydroxy-5-methoxyphenyl]methylene]-.beta.-oxo-,ethyl ester.
 38. A compound of claim 1 which is 2-thiophenepentanoicacid,α-[[3-(1,1-dimethylethyl)-4-hydroxy-5-methylphenyl]methylene]-β-oxo-,ethyl ester.
 39. A compound of claim 1 which is piperidine,1-[2-[[3,5-bis(1,1-dimethylethyl)-4-hydroxypiperidine,1-[2-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-5-(2-furanyl)-1,3-dioxopentyl]-.